医学精品课件：06 neonatal jaundice

NeonatalJaundiceProf.JialinYu余加林教授Dept.ofNeonatology,Children’sHospitalofChongqingMedicalUniversity,400014讲课内容新生儿黄疸概述胆红素代谢新生儿胆红素代谢特点新生儿黄疸分类病理性黄疸的分类新生儿肝炎新生儿溶血症发病机制ABO溶血病Rh溶血病临床表现胆红素脑病实验室检查先天性胆道闭锁母乳性黄疸遗传性疾病诊断线索与评估黄疸的治疗新生儿败血症临床表现实验室检查治疗诊断治疗病原学Neonataljaundicealsoashyperbilirubinemia,Within1weekofage，incidentofvisiblyjaundice：60%infull-terminfants，80%inpreterminfants.Introduction

PhysiologicalphenomenonPathologicsign

SignificanceofJaundiceinnewborn:

Itmaybeasignofanotherdisorder,e.g.infection

Unconjugated

bilirubincanbedepositedinthebrain,particularlyinthebasalganglia,causingkernicterus.Maydevelopintolivercirrhosisifbiliary

atresianotperform

hepatoportoenterostomyintime.urobilinogenalbuminUnconjugated(indirect)bilirubinYproteinZproteinSHOPLivercellsUnconjugated

bilirubinGlucuronyl

transferaseGlucuronicacidresiduesUnconjugated

bilirubinconjugatedbilirubinSolubleinlipidsSolubleinwaterMETABOLICPATHWAYOFBILIRUBIN间接胆红素（游离）血红素加氧酶网状内皮系统破坏衰老红细胞旁路途径血红蛋白+白蛋白间接胆红素+

y、z蛋白结合胆红素肝细胞细菌尿胆原肠肝循环大脑葡萄糖醛酸基转移酶

胆红素代谢

Morebilirubinproduction:(morebilirubinloadforliver）：anewbornproducesbilirubinof6-8mg/kg.d，aadultonly3-4mg/kg.d1．Excessiver

hematoclasis

2．Shorterredcelllifespan

3.morebypassoriginofbilirubin

①

hemeproteineg.peroxidase,cytochromeP450②

bilirubin

prosoma

←ineffectivehematopoisis

4.bilirubin-produce-enzyme:highcontentofhaemoxygenase(d1-7）Characteristic

ofneonatalbilirubinmetabolismNotenoughtransportation：plasma-albumin，orpoorboundingImmaturityofliverfunction：

1.uptake↓：Y.Zprotein↓（d5-15

reachadultlevel）

2.process↓：glucuronyl

transferase↓（about1wk↑，reachadultlevelat2wk）

3.excretion↓：easytocholestasisUnusualenterohepaticcirculation：

1．Normalflora↓，bilirubininsidegut--∥→prophobilinogen（urobinogen，stercobilinogen）

2.β-glucuronidase↑：enterohepaticcirculation↑

Characteristic

ofneonatalbilirubinmetabolismSummaryofneonatalbilirubinmetabolism↑Bilirubinload

Albuminnotenough:Defectivetransport

Immaturityofliverenzymes↑reabsorptionofbilirubinfromgutNeonatalinfantsareeasytohappenjaundiceandbecomepathologicjaundice.胆红素生成↑白蛋白联结的胆红素↓肝细胞处理胆红素↓肠肝循环↑1．Hungry：poorglucose→glucuronate↓bilirubinconjugation↓2．hypoxia：everystepsforbilirubinmetabolismneedoxygen3．constipation：

meconiumhas5-10timehigherbilirubinthanstool,enterohepaticcycle↑4．dehydration：densityofbilirubin

5．acidosis：directratiobetweenpHandbindingabilityofbilirubin

withalbuminpH7.4：bilirubin+albumin2:1(mol);pH7.0：bilirubinseparatefromalbumin6．Internalhemorrhage：hematoclasis↑AggravationfactorofneonataljaundicePhysiologicJaundice:

(alloffollowsfeature)PathologicJaundice：(anyoffollowsfeature)

jaundiceappearsin2-3doflife

jaundiceappearsin<24hoflifeFade≤14dPersistfor>2w,Totalserumbilirubin(TB):underthephototherapylevel

eg:72hoflife≤12.9mg/dl(221µmol/L)

TBoverthephototherapyleveleg:72hoflife>12.9mg/dl(221µmol/L)

NormalconditionofBB

FadedjaundiceappearsagainDirectbilirubin(DB)>2mg/dl(34µmol/L)orDB/TB>10%differentialCriteriaJaundiceinprematures？

infectious

non-infectious新生儿肝炎neonatalhepatitis新生儿败血症neonatalbacterialsepsis新生儿溶血症Hemolyticdisorders

胆道闭锁Biliary

Atresia母乳性黄疸Breastmilkjaundice遗传性疾病HereditarydiseasesClinicalClassificationofPathologicJaundice1.InfectiousJaundice：

--Neonatalhepatitis：

a.

Antipartumandintrapartuminfections

b.

Majorpathogenisvirus：CMV,hepatitisB

TORCH综合症：

T－toxoplasma,弓形体

O－others：HBV、HIV、梅毒螺旋体、肠道病毒及EB病毒等

R－rubellavirus,风疹病毒

C－Cytomegalovirus，CMV，巨细胞病毒

H－herpessimplexvirus，HSV,单纯疱疹病毒

c.

Occueyellowusuallyafter1W，whitestool，deepcolorurine，

pepatosplenomegalyd.investigationClinicalClassificationofPathologicJaundice

1.InfectiousJaundice：--Neonatalsepsis:

mechanismofjaundicehappening:toxic-hepatitis，

or/andhemolysisClinicalClassificationofPathologicJaundiceNeonatalbacterialsepsis,Septicemia新生儿病理性黄疸常见的感染性疾病

新生儿败血症Definition

定义Systemicdiseaseassociatedwiththepresenceandpersistenceofpathogenicmicroorganismsortheirtoxinsintheblood.(Dorland,27thed)病原体侵入新生儿血液循环，并在其中生长、繁殖、产生毒素而造成的全身性反应。新生儿败血症

--焦建成,余加林.新生儿败血症诊断研究进展.中华儿科杂志2010，48(1):32-35外伤sepsissepticemia新生儿败血症

--新生儿败血症

--NeonatalSepticemiaIncidence 1-4Newborns/ 1000LB/YearMeningitis 5-25%Casefatality ~25%(2-60%)新生儿败血症

--PathogenicBacteriadominativestrainsdifferentindifferentregion&eraInChina:

staphylococci(葡萄球菌)&Ecoli(大肠杆菌)

opportunistpathogen(机会致病菌)：

coagulase-negativestaphylococci,CONS(凝固酶阴性葡萄球菌)Pseudomonasaeruginosa(铜绿假单胞菌)Inwest:groupBstreptococcus,GBS、Listerella(李斯特菌)新生儿败血症

--李斯特菌Clinicalmanifestation

Earlyonsetsepsis,EOS-≤3day-antepartuminfection:A.frombloodcirculation,eg.GBS,Listerella,CampylobacterfetusB.iatrogenic,eg,punctureonamnioticfluidcavity,intrauterinetransfusion-intrapartuminfectionA.Ascendinginfection:prematureruptureofmembrane(PROM)for6-12hcouldhaveopportunity,50%incidencefor24h.Usually>18hasriskfactors

B.prolongedlabor:inhalation,ingestionC.iatrogenic:takebloodsamplefromscalp,putelectrodes,putobstetricforceps

新生儿败血症

--Clinicalmanifestation

lateonsetsepsis,LOS->3day-postpartuminfection(mostcommon)A.Staphylococcusareus:needlemouth,pressbreast,uncleancordmanagementB.iatrogenic:UVC,UAC

,Ventilation

eg.S.epidermidis,

P.aeruginosa新生儿败血症

--Clinicalmanifestation

Generalfeaturespallor,lethargy,jaundice,fever,hypothermia,temperatureinstability(note1/3ofconfirmedsepsiscasesarenormothermic)poorhandling,

hypoglycaemia

/hyperglycaemia,

bloodgasderangements

(includingacidosisandlactateaccumulation)新生儿败血症

--Investigations

bacteriologystudy1.Bloodculture(mandatory)-takesampleunderaseptictechniquebeforeadministrationofantibioticsassoonaspossible-samplesforcultureincludeCSF,serouscavityfluid,catherterend,supper

pubicaspiration,SPA2.specialantigen&DNAA.GBSandK1antigenofEcoli→counterimmunoelectrophoresis,latexagglutinationtestELISAB.polymerasechainreaction(PCR)→16SrRNAC.DNAprobe新生儿败血症

--Investigations

Non-specificmarkers1.FullBloodExamination(FBE)→WBC>12h：WBC<5×109/L；~3d：WBC>25×109/L;>3d：WBC>20×109/L2.immature/totalneutrophilsratio(I/T)≥0.163.plateletcount:＜100×109/L4.C-reactiveprotein(CRP),CRPrisesapproximately6hoursafteronsetofsepsisandreturnstonormalwithin2to7daysofsuccessfultreatment:usuallycut-off:>8mg/L;<6h：3mg/L;6-12h：5mg/L

5.PCT:新生儿败血症

--DiagnosisDefinitivediagnosis-ClinicalmanifestationpluspositivecultureClinicaldiagnosis-Clinicalmanifestationplusoneoffollows:A.Non-specificmarkerspositive≥2B.Pathogenicbacteriumantigen(+)orDNA(+)新生儿败血症

--TreatmentAntibacterialstherapy-Principleofmedication:1.Earlyassoonaspossible2.Bactericideselectedaccordingtopathogen3.Intravenously4.Combination5.EnoughdoseandcourseoftreatmentMaintenancetherapy-Intravenousimmunoglobulin(IVIG)mainlyfor①premature,

②severeinfection-Maintainhomeostasis:①correctacidosis,②electrolytebalance,③smoothmicrocirculation新生儿败血症

--2.Non-infectiousJaundice：

Ⅰ.

Hemolyticdisorders---unconjugated

bilirubinemia

A.Isoimmunization

B.G6PDdeficiency

Oxidant:antimalarials,somesulphonamides,ciprofloxacin,mothballs

C.spherocytosisClinicalClassificationofPathologicJaundice新生儿溶血病hemolyticdiseaseofnewborn,HDN新生儿病理性黄疸最常见的非感染疾病outline1.bloodtypeincompatibilitybetweenmotherandherbabybecauseofisoimmunity2.Inhemolyticdiseaseofthenewborn(1959-1977.Shanghai):ABOincompatibilityaccountfor85.3%

Rhincompatibilityaccountfor14.6%MNincompatibilityaccountfor0.1%3.Notanycaseofbloodtypeincompatibilitybetweenmotherandherbabywouldbeonsetthisdisease

新生儿溶血病--Hemolyticdisorders----

pathogenesisGeneralregularityofhemolysis

duetobloodgroupincompatibility

primary

in8-9w

stimulate

produce

stimulate

anamnestic

again

reaction

cross

placenta

SpecialbloodgroupantigenMaternalbodyBloodgroupantibody

(IgG)SameantigenMaternalbodyBloodgroupantibody

(IgG)↑↑

BloodcirculationinfetusornewbornconglutinationRBCrupture新生儿溶血病--firstst↑8-9Wagainst↑timeantidodyIgMIgGABOincompatibility:CommonlyOtypebloodinthemotherAorBtypeinfetus(AB?)SimilarAorBantigeninnatureNoABtypeinmothers,noOtypeininfants50%ofinvasion

infirst

pregnancyHemolyticdisorders----

pathogenesis新生儿溶血病--Rhimmunization

-Rhantigenonlyinrhesus&humanbeing-6kindsofantigen,antigenicityinorderD>E>C>c>e-definitionofRh+:takingDantigen,eg

DD.Dd-theoverwhelmingmajorityofHanpeoplebelongtoRh(+)-FrequencyofRh(-)variesindifferentracialgroupsHemolyticdisorders----

pathogenesis新生儿溶血病--

Rhimmunization：

UsuallynothappeninfirstpregnancyinvolvingRh+fetus:-primarysensitizationneed0.5-1mlblood,whenendstagepregnancyorruptureofplacenta→Rh(-)mother-producingIgMandalittleIgG,thendelivery.-Whenonceagainpregnancy

Rh+fetusonly0.05-0.1mlblood→

anamnesticreactionfirstst↑8-9Wagainst↑timeantidodyIgMIgGHemolyticdisorders----

pathogenesis新生儿溶血病--Rhimmunization：(specialconditions)

-Rh(+)motheralsohaveRh

incompatability

mother

Ddeeor

DDee

→Rh+fetal

DDEeor

DdEe

→Rh+→RhE

immunizationmother

Ddccor

DDcc

→Rh+

fetalDDCeor

DdCe

→Rh+→RhCimmunization

-usuallynofirstpregnancyhappen,buthaveexception(only1%)

1.ifmotherbesensitizedbyearlybloodtransfusion

2.ifmother’smotherhasRh+RBC(外祖母学说)Hemolyticdisorders----

pathogenesis新生儿溶血病--clinicalmanifestation1.Jaundice①Noyellowatbirth②ABOincompatabilitycanoccurfirstpregnancy，mostlyshowupatD2-3③Rh

immunizationusuallyinvolvedsecondpregnancy，showupat<24h,progressrapidly,mostsevere④unconjugated

bilirubin(DB/TB<10%)，

cholestasiswhenhemolysisseverely

→conjugatedbilirubin↑(DB/TB>15%)新生儿溶血病--2.Anemia:

①relative,indeterminatedegree②maynotenoughthresholdofdiagnosisforneonatalanemia

③maycauseheartfailure④maylastfor3-6wksoflife

clinicalmanifestation新生儿溶血病--3.Hepatosplenomegaly:extramedullary

hemopoiesis4.Fetalhydrops

clinicalmanifestation新生儿溶血病--

A.evidenceofhemolysis:①reticulocyte↑(d1>6%);②erythroblast↑(>10/100WBC)③DB/TB<10%

B.

bloodgroup

C.direct

Coomb’stest(directantiglobulintest,DAT)

(90%inRh,40%inABO)

D.elutiontest

→ABOincompatibility

(100%inABO)

E.freeantibodytest

→ABOincompatibility

(60%inABO)Specificinvestigations

forisoimmune

hemolysis新生儿溶血病--diagnosis

Postpartum:-jaundice

-bloodgroupsbetweenmotherandinfant

-serumantibody新生儿溶血病--diagnosisantipartum:

1.history

2.bloodgroupinpregnancywomenandherhusband

3.specialantibody:usuallythetiter↑after16wofgravidity

4.bilirubinlevelinamnioticfluidafter28w新生儿溶血病--Differentialdiagnosis

neonatalanemia:-twin–twintransfusionsyndrome

-fetal–maternaltransfusion

-internalhemorrhagePhysiologicanemiaCongenitalnephrosis

新生儿溶血病--Antipartumtreatment1.Plasmaexchange

:

objective：cleaningantibody2.Intrauteraltransfusion3.enzymeinducers:

phenobarbital

poahead1-2wks

4.Prematuredelivery:

IgG-Rh>1:32;history;fetalmaturelungtreatment新生儿溶血病--prophylaxis

whenRhD(-)miscarriageorabortionordeliveryRhD(+)

baby:

anti-D

globulinIMwithin72h新生儿溶血病--2.Non-infectiousJaundice：

Ⅱ.Biliary

Atresia:--conjugatedbilirubinemia

--graduallywhiteclay-coloredstoolsafterseveralwks

--sourcefrominteruteralinfections

--cholangitis→fibrosisofbileduct→biliary

atresia→cystofcommonbileduct.Manifestationat2woflifeobviously

--deepcolorurine

--hepatomegaly→livercirrhosis,liverfailure,hypersplenism

--malabsorptionoflipid-solublevitamin(A，D，E，K)→

nyctalopia,rickets,hemorrhage

ClinicalClassificationofPathologicJaundice2.Non-infectiousJaundice：Ⅲ.Breastmilkjaundice:

--

10%ofbreast-fedinfants,usuallyfrom4-7dto1-4monthoflife；--unconjugated

bilirubinemia.--Ifstopfeedingbreastmilkfor3~5d,TB↓50%excludeotherdiseases

cause：Glucuronyl

transferase

(β-葡萄糖醛酸苷酶)↑

whethercontinuebreastfeeding?Yes!ⅳ.Hereditarydiseases：

a.G6PDdeficiency

VitK3、K4,novobiocin(新生霉素)，lotus(川莲)，牛黄，mothball(樟脑丸）

b.spherocytosis

c.Gilbert’ssyndromClinicalClassificationofPathologicJaundice--50%die--sequelaes:cerebralpalsy,deafness,mentalretardation--CriticalthresholdofTB：342µmol/L--Usuallyoccurduringthe1~7doflife--PrematurritycanhavelowTBkernicterusThemostseverecomplication

ofjaundiceinnewborn

Encephalopathy(Kernicterus）opisthotonus,Kernicterus

manifestationclinicalstages:Warningphase:lethargy,poorsuck,

hypotonic,scream,continuefor12-24hSpasmphase:gaze,hypertonic,apnea,opisthotonas,convulsions,fever,etal.1/2-1/3deathorcontinuefor12-48hrecoveryphase:fadeawayabout2wSequelaephase:

kernicterusquadruple:

Athetosis,OcularMotilityDisorders,

hearingdisorder,Toothuraniumdysplasia

others:cerebralpalsy,Mentalretardation,convulsions急性胆红素脑病：

主要指生后1周内胆红素神经毒性引起的症状核黄疸：(慢性胆红素脑病）

最初是一个病理学名词，用来形容脑干神经核和小脑被胆红素浸染的情况，指胆红素毒性引起的慢性和永久性损害

Bilirubinencephalopathy（Kernicterus）:

relevantfactors:---concentrationofbilirubin

---howmuchunconjugated

bilirubinboundtoalbumin---degreeofmaturityofblood-brainbarrier(BBB)opisthotonus

角弓反张thebasalgangliastainedintoyellow

Bilirubinencephalopathy（Kernicterus）:

relevantfactors:---concentrationofbilirubin

---howmuchunconjugated

bilirubinboundtoalbumin---degreeofmaturityofblood-brainbarrier(BBB)

BBBTB20mg/dl？BilirubinencephalopathyinvestigationsauditoryevokedpotentialMRI图1.MRI第一次扫描T1WI苍白球对称性高信号，边界比较清楚（1A图），同时伴有T2WI苍白球对称性高信号（1B图），图C为正常T2WI苍白球信号

Differentialdiagnosis&treatmentofneonataljaundiceDifferentialdiagnosispointshistory：

1．Appear:

<24h

HDN

D2-3

physiologicjaundice，ABOincompatibility

D4-7

breastmilkjaundice，sepsis

>D7

breastmilkjaundice，sepsis，hepatitis,

biliary

atresia2．Speeddeveloping：rapid→hemolysis；slow→hepatitis，biliary

atresia3．Colorofstoolandurine4．Familyhistory：G6PDdeficiency，hepatitisB5．Birthhistory:PROM，prolongdelivery→intrapartum

infectionsEstimateserumbilirubinaccordingtoyellowdistributiononskinyellowdistributionSerumbilirubin

umol/L(±50）headandface100upper

trunk150Lowertrunk&thigh200Buttocks&belowknees250Palmofhands&foots﹥2501001502002501.bloodroutine:

2.urineroutine：uncojugated

bilirubin↑→biliary

atresia,hepatitis;urobilinogen↑→hemolysis

3.stool

routine：whiteclaylike→biliary

atresia,hepatitis；

darkcolor→hemolyticdisorders，hepatitis4.bloodor/andurinecultures:positive

→sepsis5.liverfunctiontests：

A.TB,DBB.severaltransaminatingenzymes:AST,ALTC.serialtypeAfetalproteinInvestigationsSpecial

checking

methodsforbiliary

atresia

:a.Ultrasonography:--anoninvasivetool.--Itmayexaminehepatobiliarystructureforpresenceandsizeofgallbladder,choledochalcysts.

b.LiverBiopsy：

--

themostspecificandsensitivemethodofdiagnosingbiliary

atresia--canfindthatbileductularproliferation,bileplugs,andportaltractedemaandfibrosis.--littlehapatocellulardamageandinflammation,littleportalinfiltrationwithmononuclearcells(contrastwithneonatalhepatitis)c.Laparotomy：itmustisperformedwithin2monthsandsurgicalintervention,80%couldachievebiledrainage.

InvestigationsTreatmentobjective：Searchdifferentcausesassoonaspossibleinordertotreatspecially：

1.<1wserioushyperbilirubinemiaiscontrolledasquicklyaspossibleandefficiently→preventionof

kern