醫(yī)學(xué)精品課件：06 neonatal jaundice

NeonatalJaundiceProf.JialinYu余加林教授Dept.ofNeonatology,Children’sHospitalofChongqingMedicalUniversity,400014講課內(nèi)容新生兒黃疸概述膽紅素代謝新生兒膽紅素代謝特點(diǎn)新生兒黃疸分類病理性黃疸的分類新生兒肝炎新生兒溶血癥發(fā)病機(jī)制ABO溶血病Rh溶血病臨床表現(xiàn)膽紅素腦病實(shí)驗(yàn)室檢查先天性膽道閉鎖母乳性黃疸遺傳性疾病診斷線索與評(píng)估黃疸的治療新生兒敗血癥臨床表現(xiàn)實(shí)驗(yàn)室檢查治療診斷治療病原學(xué)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間接膽紅素（游離）血紅素加氧酶網(wǎng)狀內(nèi)皮系統(tǒng)破壞衰老紅細(xì)胞旁路途徑血紅蛋白+白蛋白間接膽紅素+

y、z蛋白結(jié)合膽紅素肝細(xì)胞細(xì)菌尿膽原腸肝循環(huán)大腦葡萄糖醛酸基轉(zhuǎn)移酶

膽紅素代謝

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.膽紅素生成↑白蛋白聯(lián)結(jié)的膽紅素↓肝細(xì)胞處理膽紅素↓腸肝循環(huán)↑1．Hungry：poorglucose→glucuronate↓bilirubinconjugation↓2．hypoxia：everystepsforbilirubinmetabolismneedoxygen3．constipation：

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

5．a(chǎn)cidosis：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新生兒肝炎neonatalhepatitis新生兒敗血癥neonatalbacterialsepsis新生兒溶血癥Hemolyticdisorders

膽道閉鎖Biliary

Atresia母乳性黃疸Breastmilkjaundice遺傳性疾病HereditarydiseasesClinicalClassificationofPathologicJaundice1.InfectiousJaundice：

--Neonatalhepatitis：

a.

Antipartumandintrapartuminfections

b.

Majorpathogenisvirus：CMV,hepatitisB

TORCH綜合癥：

T－toxoplasma,弓形體

O－others：HBV、HIV、梅毒螺旋體、腸道病毒及EB病毒等

R－rubellavirus,風(fēng)疹病毒

C－Cytomegalovirus，CMV，巨細(xì)胞病毒

H－h(huán)erpessimplexvirus，HSV,單純皰疹病毒

c.

Occueyellowusuallyafter1W，whitestool，deepcolorurine，

pepatosplenomegalyd.investigationClinicalClassificationofPathologicJaundice

1.InfectiousJaundice：--Neonatalsepsis:

mechanismofjaundicehappening:toxic-hepatitis，

or/andhemolysisClinicalClassificationofPathologicJaundiceNeonatalbacterialsepsis,Septicemia新生兒病理性黃疸常見的感染性疾病

新生兒敗血癥Definition

定義Systemicdiseaseassociatedwiththepresenceandpersistenceofpathogenicmicroorganismsortheirtoxinsintheblood.(Dorland,27thed)病原體侵入新生兒血液循環(huán)，并在其中生長(zhǎng)、繁殖、產(chǎn)生毒素而造成的全身性反應(yīng)。新生兒敗血癥

--焦建成,余加林.新生兒敗血癥診斷研究進(jìn)展.中華兒科雜志2010，48(1):32-35外傷sepsissepticemia新生兒敗血癥

--新生兒敗血癥

--NeonatalSepticemiaIncidence 1-4Newborns/ 1000LB/YearMeningitis 5-25%Casefatality ~25%(2-60%)新生兒敗血癥

--PathogenicBacteriadominativestrainsdifferentindifferentregion&eraInChina:

staphylococci(葡萄球菌)&Ecoli(大腸桿菌)

opportunistpathogen(機(jī)會(huì)致病菌)：

coagulase-negativestaphylococci,CONS(凝固酶陰性葡萄球菌)Pseudomonasaeruginosa(銅綠假單胞菌)Inwest:groupBstreptococcus,GBS、Listerella(李斯特菌)新生兒敗血癥

--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

新生兒敗血癥

--Clinicalmanifestation

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

,Ventilation

eg.S.epidermidis,

P.aeruginosa新生兒敗血癥

--Clinicalmanifestation

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

hypoglycaemia

/hyperglycaemia,

bloodgasderangements

(includingacidosisandlactateaccumulation)新生兒敗血癥

--Investigations

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

pubicaspiration,SPA2.specialantigen&DNAA.GBSandK1antigenofEcoli→counterimmunoelectrophoresis,latexagglutinationtestELISAB.polymerasechainreaction(PCR)→16SrRNAC.DNAprobe新生兒敗血癥

--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:新生兒敗血癥

--DiagnosisDefinitivediagnosis-ClinicalmanifestationpluspositivecultureClinicaldiagnosis-Clinicalmanifestationplusoneoffollows:A.Non-specificmarkerspositive≥2B.Pathogenicbacteriumantigen(+)orDNA(+)新生兒敗血癥

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

②severeinfection-Maintainhomeostasis:①correctacidosis,②electrolytebalance,③smoothmicrocirculation新生兒敗血癥

--2.Non-infectiousJaundice：

Ⅰ.

Hemolyticdisorders---unconjugated

bilirubinemia

A.Isoimmunization

B.G6PDdeficiency

Oxidant:antimalarials,somesulphonamides,ciprofloxacin,mothballs

C.spherocytosisClinicalClassificationofPathologicJaundice新生兒溶血病hemolyticdiseaseofnewborn,HDN新生兒病理性黃疸最常見的非感染疾病outline1.bloodtypeincompatibilitybetweenmotherandherbabybecauseofisoimmunity2.Inhemolyticdiseaseofthenewborn(1959-1977.Shanghai):ABOincompatibilityaccountfor85.3%

Rhincompatibilityaccountfor14.6%MNincompatibilityaccountfor0.1%3.Notanycaseofbloodtypeincompatibilitybetweenmotherandherbabywouldbeonsetthisdisease

新生兒溶血病--Hemolyticdisorders----

pathogenesisGeneralregularityofhemolysis

duetobloodgroupincompatibility

primary

in8-9w

stimulate

produce

stimulate

anamnestic

again

reaction

cross

placenta

SpecialbloodgroupantigenMaternalbodyBloodgroupantibody

(IgG)SameantigenMaternalbodyBloodgroupantibody

(IgG)↑↑

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

infirst

pregnancyHemolyticdisorders----

pathogenesis新生兒溶血病--Rhimmunization

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

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

pathogenesis新生兒溶血病--

Rhimmunization：

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

Rh+fetusonly0.05-0.1mlblood→

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

pathogenesis新生兒溶血病--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(外祖母學(xué)說(shuō))Hemolyticdisorders----

pathogenesis新生兒溶血病--clinicalmanifestation1.Jaundice①Noyellowatbirth②ABOincompatabilitycanoccurfirstpregnancy，mostlyshowupatD2-3③Rh

immunizationusuallyinvolvedsecondpregnancy，showupat<24h,progressrapidly,mostsevere④unconjugated

bilirubin(DB/TB<10%)，

cholestasiswhenhemolysisseverely

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

①relative,indeterminatedegree②maynotenoughthresholdofdiagnosisforneonatalanemia

③maycauseheartfailure④maylastfor3-6wksoflife

clinicalmanifestation新生兒溶血病--3.Hepatosplenomegaly:extramedullary

hemopoiesis4.Fetalhydrops

clinicalmanifestation新生兒溶血病--

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新生兒溶血病--diagnosis

Postpartum:-jaundice

-bloodgroupsbetweenmotherandinfant

-serumantibody新生兒溶血病--diagnosisantipartum:

1.history

2.bloodgroupinpregnancywomenandherhusband

3.specialantibody:usuallythetiter↑after16wofgravidity

4.bilirubinlevelinamnioticfluidafter28w新生兒溶血病--Differentialdiagnosis

neonatalanemia:-twin–twintransfusionsyndrome

-fetal–maternaltransfusion

-internalhemorrhagePhysiologicanemiaCongenitalnephrosis

新生兒溶血病--Antipartumtreatment1.Plasmaexchange

:

objective：cleaningantibody2.Intrauteraltransfusion3.enzymeinducers:

phenobarbital

poahead1-2wks

4.Prematuredelivery:

IgG-Rh>1:32;history;fetalmaturelungtreatment新生兒溶血病--prophylaxis

whenRhD(-)miscarriageorabortionordeliveryRhD(+)

baby:

anti-D

globulinIMwithin72h新生兒溶血病--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(川蓮)，牛黃，mothball(樟腦丸）

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急性膽紅素腦?。?/p>

主要指生后1周內(nèi)膽紅素神經(jīng)毒性引起的癥狀核黃疸：(慢性膽紅素腦病）

最初是一個(gè)病理學(xué)名詞，用來(lái)形容腦干神經(jīng)核和小腦被膽紅素浸染的情況，指膽紅素毒性引起的慢性和永久性損害

Bilirubinencephalopathy（Kernicterus）:

relevantfactors:---concentrationofbilirubin

---howmuchunconjugated

bilirubinboundtoalbumin---degreeofmaturityofblood-brainbarrier(BBB)opisthotonus

角弓反張thebasalgangliastainedintoyellow

Bilirubinencephalopathy（Kernicterus）:

relevantfactors:---concentrationofbilirubin

---howmuchunconjugated

bilirubinboundtoalbumin---degreeofmaturityofblood-brainbarrier(BBB)

BBBTB20mg/dl？BilirubinencephalopathyinvestigationsauditoryevokedpotentialMRI圖1.MRI第一次掃描T1WI蒼白球?qū)ΨQ性高信號(hào)，邊界比較清楚（1A圖），同時(shí)伴有T2WI蒼白球?qū)ΨQ性高信號(hào)（1B圖），圖C為正常T2WI蒼白球信號(hào)

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