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Diagnosticapproachtotheadultwithjaundiceorasymptomatichyperbilirubinemia
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Apr2016.|Thistopiclastupdated:Jan29,2014.
INTRODUCTIONJaundiceandasymptomatichyperbilirubinemiaarecommonclinicalproblemsthatcanbe
causedbyavarietyofdisorders,includingbilirubinoverproduction,impairedbilirubinconjugation,biliary
obstruction,andhepaticinflammation.(See"Classificationandcausesofjaundiceorasymptomatic
hyperbilirubinemia".)
Thistopicwillprovideanoverviewofthediagnosticapproachtoadultswithjaundiceorasymptomatic
hyperbilirubinemia.Thecausesofjaundiceandasymptomatichyperbilirubinemia,detaileddiscussionsofthe
specifictestingused,andtheevaluationofpatientswithotherlivertestabnormalitiesarediscussedelsewhere.
(See"Classificationandcausesofjaundiceorasymptomatichyperbilirubinemia"and"Approachtothepatientwith
abnormalliverbiochemicalandfunctiontests".)
REFERENCERANGESLivertestreferencerangeswillvaryfromlaboratorytolaboratory.Asanexample,one
hospital'snormalreferencerangesforadultsareasfollows[1]:
Albumin:3.3to5.0g/dL(33to50g/L)
Alkalinephosphatase:
Male:45to115int.unit/L
Female:30to100int.unit/L
Alanineaminotransferase(ALT):
Male:10to55int.unit/L
Female:7to30int.unit/L
Aspartateaminotransferase(AST):
Male:10to40int.unit/L
Female:9to32int.unit/L
Bilirubin,total:0.0to1.0mg/dL(0to17micromol/L)
Bilirubin,direct:0.0to0.4mg/dL(0to7micromol/L)
Gammaglutamyltranspeptidase(GGT):
Male:8to61int.unit/L
Female:5to36int.unit/L
Prothrombintime(PT):11.0to13.7seconds
CAUSESOFHYPERBILIRUBINEMIAForclinicalpurposes,serumbilirubinisfractionatedtoclassify
hyperbilirubinemiaintooneoftwomajorcategories(table1)(see"Clinicalaspectsofserumbilirubin
determination"):
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Plasmaelevationofpredominantlyunconjugated(indirect)bilirubin.Thismaybeduetotheoverproductionof
bilirubin,impairedbilirubinuptakebytheliver,orabnormalitiesofbilirubinconjugation(algorithm1).
Plasmaelevationofbothunconjugatedandconjugated(direct)bilirubin.Thismaybeduetohepatocellular
disease,impairedcanalicularexcretionofbilirubin,orbiliaryobstruction(algorithm2).Thisisoftenreferredto
asconjugatedhyperbilirubinemia,eventhoughbothfractionsofbilirubinareelevated.
Oncethehyperbilirubinemiahasbeenclassified,thedifferentialdiagnosiscanbenarrowed.(See"Classification
andcausesofjaundiceorasymptomatichyperbilirubinemia".)
Unconjugatedhyperbilirubinemiamaybecausedby(table1):
Hemolysis
Extravasationofbloodintotissue
Dyserythropoiesis
Stresssituations(eg,sepsis)leadingtoincreasedproductionofbilirubin
Impairedhepaticbilirubinuptake
Impairedbilirubinconjugation
Conjugatedhyperbilirubinemiamaybecausedby(table1andtable2):
Biliaryobstruction(eg,gallstones,pancreaticorbiliarymalignancy,AIDScholangiopathy,parasites)
Viralhepatitis
Alcoholichepatitis
Nonalcoholicsteatohepatitis
Primarybiliarycirrhosis
Drugsandtoxins
Ischemichepatopathy
Liverinfiltration
Inheriteddisorders(eg,DubinJohnsonsyndrome,Rotorsyndrome,progressivefamilialintrahepatic
cholestasis)
Totalparenteralnutrition
Postoperativejaundice
Intrahepaticcholestasisofpregnancy
Endstageliverdisease
Organtransplantation(eg,bonemarrow,liver)
Thefrequencywithwhichthedifferentcausesoccurvarieswithageandthepopulationbeingstudied.Onereport,
forexample,evaluatedtheprincipaldiagnosesobtainedin702adultspresentingwithjaundiceto24Dutch
hospitalsoveratwoyearperiod[2].Pancreaticorbiliarycarcinomaaccountedfor20percent,gallstonesfor13
percent,andalcoholiccirrhosisfor10percent.
Insomecases,twoormorefactorscontributetothedevelopmentofjaundice.Thisisparticularlytrueinthe
followingsettings:sicklecellanemia,organtransplantationorsurgeryingeneral,totalparenteralnutrition,and
AIDS.Whenevaluatingthesepatients,itisnecessarytotakeintoaccounttheunderlyingillness,thetypeof
therapyadministered(eg,drugs,surgery),andthepossibleassociatedcomplications.
DIAGNOSTICEVALUATIONThediagnosticapproachtothejaundicedpatientbeginswithacarefulhistory,
physicalexamination,andinitiallaboratorystudies.Adifferentialdiagnosisisformulatedbasedonthoseresults
andadditionaltestingisperformedtonarrowthediagnosticpossibilities.
Althoughtheevaluationisusuallynoturgent,jaundicecanreflectamedicalemergencyinafewsituations.These
includemassivehemolysis(eg,duetoClostridiumperfringenssepsisorfalciparummalaria),ascending
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cholangitis,andfulminanthepaticfailure.Expedientdiagnosisandappropriatetherapycanbelifesavinginthese
settings.
HistoryandphysicalexaminationMultiplecluestotheetiologyofapatientshyperbilirubinemiacanbe
obtainedfromthehistory,whichshouldseekthefollowinginformation(see"Approachtothepatientwithabnormal
liverbiochemicalandfunctiontests",sectionon'History'):
Useofmedications,herbalmedications,dietarysupplements,andrecreationaldrugs
Useofalcohol
Hepatitisriskfactors(eg,travel,possibleparenteralexposures)
Historyofabdominaloperations,includinggallbladdersurgery
Historyofinheriteddisorders,includingliverdiseasesandhemolyticdisorders
HIVstatus
Exposuretotoxicsubstances
Associatedsymptoms
Associatedsymptomsoftenhelpnarrowthedifferentialdiagnosis.Asexamples:
Ahistoryoffever,particularlywhenassociatedwithchillsorrightupperquadrantpainand/orahistoryof
priorbiliarysurgery,issuggestiveofacutecholangitis.
Symptomssuchasanorexia,malaise,andmyalgiasmaysuggestviralhepatitis.
Rightupperquadrantpainsuggestsextrahepaticbiliaryobstruction.
Acholicstool(alsotermedclaycoloredstool)referstostoolwithouttheyellowbrowncolor,whichisnormally
derivedmainlyfromthebilirubinbreakdownproducts,urobilinandstercobilin.Althoughrare,itcanalsobe
seenintheacutecholestaticphaseofviralhepatitisandinprolongednearcompletecommonbileduct
obstructionfromcancerofthepancreaticheadortheduodenalampulla.
ThephysicalexaminationmayrevealaCourvoisiersign(apalpablegallbladder,causedbyobstructiondistaltothe
takeoffofthecysticductbymalignancy)orsignsofchronicliverfailure/portalhypertensionsuchasascites,
splenomegaly,spiderangiomata,andgynecomastia.Certainfindingssuggestspecificdiseases,suchas
hyperpigmentationinhemochromatosis,KayserFleischerringsinWilsondisease,andxanthomasinprimary
biliarycirrhosis.(See"Approachtothepatientwithabnormalliverbiochemicalandfunctiontests",sectionon
'Physicalexamination'.)
InitiallaboratorytestsInitiallaboratorytestsincludemeasurementsofserumtotalandunconjugatedbilirubin,
alkalinephosphatase,aminotransferases(aspartateaminotransferase[AST]andalanineaminotransferase[ALT]),
prothrombintime/internationalnormalizedratio(INR),andalbumin.Thepresenceorabsenceofabnormalitiesand
thetypeofabnormalitiesshouldhelptodistinguishthevariouscausesofjaundice.(See"Approachtothepatient
withabnormalliverbiochemicalandfunctiontests",sectionon'Laboratorytests'.)
However,whilelivertestsprovideabroadguidelinefortheinitialdistinctionbetweenthedifferentcausesof
jaundice,exceptionsdooccur.Asanexample,viralhepatitis,whichnormallypresentsprimarilywithanelevation
ofserumaminotransferases,maypresentasapredominantlycholestaticsyndromewithmarkedpruritus.
NormalalkalinephosphataseandaminotransferasesIfthealkalinephosphataseandaminotransferases
arenormal,thejaundiceislikelynotduetohepaticinjuryorbiliarytractdisease.Insuchpatients,hemolysisor
inheriteddisordersofbilirubinmetabolismmayberesponsibleforthehyperbilirubinemia.Theinheriteddisorders
associatedwithisolatedunconjugatedhyperbilirubinemiaareGilbertandCriglerNajjarsyndromesthedisorders
associatedwithisolatedconjugatedhyperbilirubinemiaareRotorandDubinJohnsonsyndromes.(See"Approach
tothediagnosisofhemolyticanemiaintheadult"and"Gilbertsyndromeandunconjugatedhyperbilirubinemiadue
tobilirubinoverproduction"and"CriglerNajjarsyndrome".)
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PredominantalkalinephosphataseelevationElevationoftheserumalkalinephosphataseoutof
proportiontotheserumaminotransferasessuggestsbiliaryobstructionorintrahepaticcholestasis.Increased
serumalkalinephosphataseisalsofoundingranulomatousliverdiseases,suchastuberculosisorsarcoidosis.
Theseconditionsmayormaynotbeassociatedwithjaundice.(See"Approachtothepatientwithabnormalliver
biochemicalandfunctiontests",sectionon'Elevatedalkalinephosphatase'.)
Anelevationintheserumalkalinephosphataseconcentrationcanalsobederivedfromextrahepatictissues,
particularlybone.Extrahepaticdisordersdonotcausejaundiceexceptinrarecases,suchasbonetumors
metastasizingtotheliver.Ifnecessary,theserumactivitiesofthecanalicularenzymesgammaglutamyl
transpeptidase(GGT)and5'nucleotidasecanbemeasuredtoconfirmthehepaticoriginofalkalinephosphatase
(algorithm3).(See"Enzymaticmeasuresofcholestasis(eg,alkalinephosphatase,5'nucleotidase,gamma
glutamyltranspeptidase)".)
PredominantaminotransferaseelevationApredominantelevationofserumaminotransferaseactivity
suggeststhatjaundiceiscausedbyintrinsichepatocellulardisease(table2).Thepatternoftheelevationmayhelp
identifyaspecificcause.(See"Approachtothepatientwithabnormalliverbiochemicalandfunctiontests",
sectionon'Laboratorytests'.)
Asanexample,alcoholichepatitisisassociatedwithadisproportionateelevationoftheASTcomparedwiththe
ALT.TheASTelevationisusuallylessthaneighttimestheupperlimitofnormal,andtheALTelevationistypically
lessthanfivetimestheupperlimitofnormal.TheASTtoALTratioisusuallygreaterthan2.0,avaluerarelyseen
inotherformsofliverdisease.(See"Clinicalmanifestationsanddiagnosisofalcoholicfattyliverdiseaseand
alcoholiccirrhosis",sectionon'Livertestabnormalities'.)
ElevatedINRAnelevatedINRthatcorrectswithvitaminKadministrationsuggestsimpairedintestinal
absorptionoffatsolublevitaminsandiscompatiblewithobstructivejaundice.Ontheotherhand,anelevatedINR
thatdoesnotcorrectwithvitaminKsuggestsmoderatetoseverehepatocellulardiseasewithimpairedsynthetic
function(particularlyifunexplainedhypoalbuminemiaisalsopresent).
SubsequentevaluationSubsequentstudiesareguidedbasedonfindingsfromthehistory,physical
examination,andinitiallaboratorytests.
UnconjugatedhyperbilirubinemiaTheevaluationofunconjugatedhyperbilirubinemiatypicallyinvolves
evaluationforhemolyticanemia,drugsthatimpairhepaticuptakeofbilirubin,andGilbertsyndrome(algorithm1).
InapatientwithahistoryconsistentwithGilbertsyndrome(eg,thedevelopmentofjaundiceduringtimesof
stress)additionaltestingisnotrequired.Ifthisinitialevaluationisnegativeandtheunconjugated
hyperbilirubinemiapersists,othercausesshouldbesought(eg,CriglerNajjarsyndrome).(See"Approachtothe
patientwithabnormalliverbiochemicalandfunctiontests",sectionon'Unconjugated(indirect)hyperbilirubinemia'.)
ConjugatedhyperbilirubinemiaInpatientswithconjugatedhyperbilirubinemia,theevaluationwillbe
basedonwhethertheabnormalitiesarelikelyduetobiliaryobstruction,intrahepaticcholestasis,hepatocellular
injury,oraninheritedcondition(basedonthepresenceofisolatedconjugatedhyperbilirubinemia)(algorithm2).
SuspectedbiliaryobstructionorintrahepaticcholestasisIfthereisevidenceofbiliaryobstructionor
intrahepaticcholestasis(eg,elevatedconjugatedbilirubinandalkalinephosphatase),thefirststepintheevaluation
ishepaticimaging(eg,ultrasound,magneticresonancecholangiopancreatography[MRCP],endoscopicretrograde
cholangiopancreatography[ERCP])tolookforevidenceofintraorextrahepaticbileductdilation[3].Ifimagingis
negative,theevaluationtypicallywillalsoincludeobtaininganantimitochondrialantibodytoevaluateforprimary
biliarycirrhosis.(See"Approachtothepatientwithabnormalliverbiochemicalandfunctiontests",sectionon
'Evaluationofelevatedalkalinephosphatase'.)
Inmostinstances,abdominalultrasound(andlessoftenspiralcomputedtomography[CT]scan)isthefirst
imagingtestobtainedinpatientswithsuspectedbiliaryobstructionwithunknownetiology[3].(See"Approachto
thepatientwithabnormalliverbiochemicalandfunctiontests",sectionon'Evaluationofelevatedalkaline
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phosphatase'.)
However,insomecases,otherimagingstudiesmaybemoreappropriateasinitialtests:
Inthepatientwithalowprobabilityofobstruction,abdominalCTshouldbeperformedand,intheabsenceof
evidenceofobstruction,furtherevaluationshouldbedirectedtowardscausesofhepatocellulardisease.If,
ontheotherhand,dilatedbiliaryductsarevisualized,directimagingofthebiliarytree(eg,withERCP)
shouldbeperformed.
Inthepatientwithahighexpectationofextrahepaticobstruction,endoscopicultrasound(EUS)orERCPcan
betheinitialscreeningprocedure,sinceanegativeUSwouldnotprecludethesubsequentperformanceof
ERCP.Onestudyperformedpercutaneoustranshepaticcholangiography(PTC)in107patientswithclinically
suspectedbileductabnormalitiesbutnondilatedintrahepaticductsonCTorultrasound[4].The
cholangiogramwasdiagnosticin72patients(67percent)and31(43percent)showedpooremptying,stones,
orstrictures.Becauseofahighrateofcomplications,theauthorstosuggestthatERCPwaspreferableto
PTCinpatientswithnondilatedducts.
Inthepatientwithevidenceofobstructionbutlittleclueastothedistinctionbetweenintrahepaticand
extrahepaticdisease,ascreeningultrasoundmayprovideinformationusefulindeterminingtheoptimaluseof
EUSorERCPversusintrahepaticcholangiography.DecisionanalysisstudiessuggestthatEUSmaybe
preferredinthissettingwhenthereisanintermediateprobabilityofobstruction[5].
Theimagingtestsusedintheevaluationofbiliaryobstructionarediscussedindetailelsewhere.(See
"Choledocholithiasis:Clinicalmanifestations,diagnosis,andmanagement",sectionon'Imagingtest
characteristics'and"Ultrasonographyofthehepatobiliarytract"and"Computedtomographyofthehepatobiliary
tract"and"Magneticresonancecholangiopancreatography"and"Endoscopicretrogradecholangiopancreatography:
Indications,patientpreparation,andcomplications"and"Endoscopicultrasoundinpatientswithsuspected
choledocholithiasis"and"Percutaneoustranshepaticcholangiography".)
SuspectedhepatocellularinjuryIfthereisevidenceofhepatocellularinjury(eg,apredominant
elevationofserumaminotransferases),serologictestingshouldbeperformedtoevaluateforcausesof
hepatocellulardysfunction.(See'Predominantaminotransferaseelevation'aboveand"Approachtothepatientwith
abnormalliverbiochemicalandfunctiontests",sectionon'Elevatedserumaminotransferases'and"Cirrhosisin
adults:Etiologies,clinicalmanifestations,anddiagnosis",sectionon'Determiningthecauseofcirrhosis'.)
Testingshouldinclude:
Serologictestsforviralhepatitis
Measurementofantimitochondrialantibodies(forprimarybiliarycirrhosis)
Measurementofantinuclearantismoothmuscleandliverkidneymicrosomalantibodies(forautoimmune
hepatitis)
Serumlevelsofiron,transferrin,andferritin(forhemochromatosis)
Thyroidfunctiontests
Antibodyscreeningforceliacdisease
Additionaltestingmayalsoinclude(basedontheclinicalscenario):
Serumlevelsofceruloplasmin(forWilsondisease)
Measurementofalpha1antitrypsinactivity(foralpha1antitrypsindeficiency)
Testingforadrenalinsufficiency
Insomecases,liverbiopsymayberequiredtoconfirmthediagnosis.
IsolatedconjugatedhyperbilirubinemiaConjugatedhyperbilirubinemiawithoutotherroutinelivertest
abnormalitiesisfoundintworareinheritedconditions:DubinJohnsonsyndromeandRotorsyndrome.Dubin
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JohnsonsyndromeandRotorsyndromeshouldbesuspectedinpatientswithmildhyperbilirubinemia(witha
conjugatedfractionofapproximately50percent)intheabsenceofotherabnormalitiesofstandardliver
biochemicaltests.NormallevelsofserumalkalinephosphataseandGGThelptodistinguishtheseconditionsfrom
disordersassociatedwithbiliaryobstruction.Differentiatingbetweenthesesyndromesispossiblebutclinically
unnecessaryduetotheirbenignnature.(See"Inheriteddisordersassociatedwithconjugatedhyperbilirubinemia".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
"patientinfo"andthekeyword(s)ofinterest.)
Basicstopic(see"Patientinformation:Jaundiceinadults(TheBasics)")
SUMMARYANDRECOMMENDATIONS
Forclinicalpurposes,serumbilirubinisfractionatedtoclassifyhyperbilirubinemiaintooneoftwomajor
categories:unconjugated(indirect)hyperbilirubinemiaandconjugated(direct)hyperbilirubinemia(table1).
Thisclassification,alongwithfindingsfromthehistory,physicalexamination,andinitiallaboratorytestingis
usedtonarrowthediagnosticpossibilitiesandguidethesubsequentevaluation.(See'Causesof
hyperbilirubinemia'above.)
Multiplecluestotheetiologyofhyperbilirubinemiacanbeobtainedfromthehistory,whichshouldseekthe
followinginformation(see'Historyandphysicalexamination'above):
Useofmedicationsorrecreationaldrugs(see"Druginducedliverinjury")
Useofdietarysupplementsorherbalmedications(see"Hepatotoxicityduetoherbalmedicationsand
dietarysupplements")
Useofalcohol(see"Screeningforunhealthyuseofalcoholandotherdrugsinprimarycare")
Hepatitisriskfactors(eg,travel,parenteralexposure)
Historyofabdominaloperations,includinggallbladdersurgery
Historyofinheriteddisordersincludingliverdiseasesandhemolyticdisorders
HIVstatus
Exposuretotoxicsubstances
Initiallaboratorytestsincludemeasurementsofserumtotalandunconjugatedbilirubin,alkalinephosphatase,
aminotransferases(aspartateaminotransferaseandalanineaminotransferase),prothrombintime/international
normalizedratio(INR),andalbumin.Thepresenceorabsenceofabnormalitiesandthetypeofabnormalities
helpdistinguishthevariouscausesofjaundice(algorithm1andalgorithm2).
Ifthealkalinephosphataseandaminotransferasesarenormal,thejaundiceislikelynotduetohepatic
injuryorbiliarytractdisease.Insuchpatients,hemolysisorinheriteddisordersofbilirubinmetabolism
mayberesponsibleforthehyperbilirubinemia.(See'Normalalkalinephosphataseand
aminotransferases'above.)
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Elevationoftheserumalkalinephosphataseoutofproportiontotheserumaminotransferasessuggests
biliaryobstructionorintrahepaticcholestasis.(See'Predominantalkalinephosphataseelevation'
above.)
Apredominantelevationofserumaminotransferaseactivitysuggeststhatjaundiceiscausedby
intrinsichepatocellulardisease(table2).(See'Predominantaminotransferaseelevation'above.)
AnelevatedINRthatcorrectswithvitaminKadministrationsuggestsimpairedintestinalabsorptionof
fatsolublevitaminsandiscompatiblewithobstructivejaundice.Ontheotherhand,anelevatedINR
thatdoesnotcorrectwithvitaminKsuggestsmoderatetoseverehepatocellulardiseasewithimpaired
syntheticfunction(particularlyifunexplainedhypoalbuminemiaisalsopresent).(See'ElevatedINR'
above.)
Theevaluationofunconjugatedhyperbilirubinemiatypicallyinvolvesevaluationforhemolyticanemia,drugs
thatimpairhepaticuptakeofbilirubin,andGilbertsyndrome(algorithm1).(See'Unconjugated
hyperbilirubinemia'above.)
Ifthereisevidenceofbiliaryobstructionorintrahepaticcholestasis(eg,elevatedconjugatedbilirubinand
alkalinephosphatase),thefirststepintheevaluationishepaticimaging(eg,ultrasound,magneticresonance
cholangiopancreatography[MRCP],endoscopicretrogradecholangiopancreatography[ERCP])tolookfor
evidenceofintraorextrahepaticbileductdilation.Ifimagingisnegative,theevaluationtypicallywillalso
includeobtaininganantimitochondrialantibodytoevaluateforprimarybiliarycirrhosis.(See'Suspected
biliaryobstructionorintrahepaticcholestasis'above.)
Ifthereisevidenceofhepatocellularinjury(eg,apredominantelevationofserumaminotransferases),
serologictestingshouldbeperformedtoevaluateforcausesofhepatocellulardysfunction,suchasviral
hepatitis,alcoholicliverdisease,andmetabolicliverdisease(table2andtable3).(See'Suspected
hepatocellularinjury'above.)
Conjugatedhyperbilirubinemiawithoutotherroutinelivertestabnormalitiesisfoundintworareinherited
conditions:DubinJohnsonsyndromeandRotorsyndrome.Normallevelsofserumalkalinephosphataseand
gammaglutamyltranspeptidasehelpdistinguishtheseconditionsfromdisordersassociatedwithbiliary
obstruction.(See'Isolatedconjugatedhyperbilirubinemia'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1.http://mghlabtest.partners.org/MGH_Reference_Intervals_August_2011.pdf(AccessedonMarch29,2013).
2.ReismanY,GipsCH,LavelleSM,WilsonJH.Clinicalpresentationof(subclinical)jaundicetheEuricterus
projectinTheNetherlands.UnitedDutchHospitalsandEuricterusProjectManagementGroup.
Hepatogastroenterology199643:1190.
3.SainiS.Imagingofthehepatobiliarytract.NEnglJMed1997336:1889.
4.TeplickSK,FlickP,BrandonJC.Transhepaticcholangiographyinpatientswithsuspectedbiliarydisease
andnondilatedintrahepaticbileducts.GastrointestRadiol199116:193.
5.SahaiAV,MauldinPD,MarsiV,etal.Bileductstonesandlaparoscopiccholecystectomy:adecision
analysistoassesstherolesofintraoperativecholangiography,EUS,andERCP.GastrointestEndosc1999
49:334.
Topic3620Version13.0
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GRAPHICS
Classificationofjaundiceaccordingtotypeofbilepigmentand
mechanism
Unconjugatedhyperbilirubinemia Conjugatedhyperbilirubinemia
Increasedbilirubinproduction* Extrahepaticcholestasis(biliary
obstruction)
Extravascularhemolysis
Choledocholithiasis
Extravasationofbloodintotissues
Intrinsicandextrinsictumorseg,
Intravascularhemolysis
cholangiocarcinoma
Dyserythropoiesis
Primarysclerosingcholangitis
Impairedhepaticbilirubinuptake
AIDScholangiopathy
Heartfailure
Acuteandchronicpancreatitis
Portosystemicshunts
Stricturesafterinvasiveprocedures
SomepatientswithGilbertsyndrome
Certainparasiticinfectionseg,Ascaris
Certaindrugs rifampin,probenecid, lumbricoides,liverflukes
flavaspadicacid,bunamiodyl
Intrahepaticcholestasis
Impairedbilirubinconjugation
Viralhepatitis
CriglerNajjarsyndrometypesIandII
Alcoholichepatitis
Gilbertsyndrome
Nonalcoholicsteatohepatitis
Neonates
Chronichepatitis
Hyperthyroidism
Primarybiliarycholangitis
Ethinylestradiol
Drugsandtoxinseg,alkylatedsteroids,
Liverdiseaseschronichepatitis,advanced chlorpromazine,herbalmedications(eg,
cirrhosis,Wilsondisease Jamaicanbushtea),arsenic
Sepsisandhypoperfusionstates
Infiltrativediseaseseg,amyloidosis,
lymphoma,sarcoidosis,tuberculosis
Totalparenteralnutrition
Postoperativecholestasis
Followingorgantransplantation
Hepaticcrisisinsicklecelldisease
Pregnancy
Endstageliverdisease
AIDS:acquiredimmunodeficiencysyndrome.
*Serumbilirubinconcentrationusuallylessthan4mg/dL(68mmol/L)intheabsenceofunderlyingliver
disease.
Thehyperbilirubinemiainducedbydrugsusuallyresolveswithin48hoursafterthedrugis
discontinued.
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Graphic55607Version6.0
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Classificationofjaundiceduetomainlyunconjugatedhyperbilirubinemia
Graphic50896Version5.0
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Classificationofjaundiceduetobothconjugated
andunconjugatedhyperbilirubinemia
Graphic62683Version5.0
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Differentialdiagnosisofhepatocellularjaundice
Neoplasms Infections
Hepatocellularcarcinoma Viral
Cholangiocarcinoma Hepatitisviruses
Metastases(bronchogenic,GI Herpesviruses
tract,breast,GUtract)
"Hemorrhagic"viruses:yellowfever,Ebola,Marburg,Lassa
Lymphoma
Adenoviruses,enteroviruses,etc
Hemangioendothelioma
Bacterial
Hepatoblastoma
Tuberculosis,leptospirosis,syphilis,pyogenicabscess,
Metabolic/hereditary Brucella,Rickettsia,Tropherymawhippeli,Rochalimea
Wilsondisease Parasitic
Alpha1antitrypsindeficiency Helminths:Ascaris,Fasciola,Clonorchis,schistosomiasis,
echinococcosis
Hemochromatosis
Protozoa:amebiasis,plasmodia,babesiosis,toxoplasmosis,
Porphyrias
leishmaniasis
Congenitalhepaticfibrosis
Fungal
Fibropolycysticdisease
Candida,Blastomyces,Coccidioides,Histoplasma,
Systemic Cryptococcus
Acuteischemia Toxic/immunologic
Severeheartfailure Medications(allergic,idiosyncratic)
Tricuspidinsufficiency Alcohol
Constrictivepericarditis Chlorinatedhydrocarbons(carbontetrachloride,chloroform)
BuddChiarisyndrome Amanitaphalloidestoxin
Venoocclusivedisease AflatoxinB1
Telangiectasias VitaminA
Sarcoidosis Pyrrolizidinealkaloids
Amyloidosis Arsenic
Miscellaneous Phosphorous
Secondarybiliarycirrhosis Autoimmunehepatitis
Cryptogeniccirrhosis Primarybiliarycholangitis
Primarysclerosingcholangitis
Overlapsyndrome
Autoimmunecholangiopathy
Nonalcoholicsteatohepatitis
GI:gastrointestinalGU:genitourinary.
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Evaluationofelevatedserumalkalinephosphatase
AMA:antimitochondrialantibodiesERCP:endoscopicretrograde
cholangiopancreatographyMRCP:magneticresonance
cholangiopancreatographyULN:upperlimitofnormal.
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Commoncausesofabnormalliverbloodtests
Disease Testsandfindings
Alcoholicliver Historyofalcoholabuse
disease
AST/ALT>2withbothbeinglessthan500internationalunit/mLifalcoholic
hepatitisispresent
Chronichepatitis ELISAassayforantiHCV
C
PCRforHCVRNAifconfirmatorytestisnecessary
Primarybiliary Antimitochondrialantibodiesasanisolatedfinding
cholangitis
IgMelevation
Primary Strongassociationwithinflammatoryboweldisease
sclerosing
Cholangiographytoestablishthediagnosis
cholangitis
AntinuclearandantismoothmuscleantibodiesandANCAthesearenot
diagnostic
Autoimmune Hypergammaglobulinemia
hepatitis
AntinuclearandsmoothmuscleantibodiesandANCAintype1antiLKM1in
type2
Chronichepatitis HBsAgandHBeAgand,insomecases,HBVDNAbyhybridizationorbDNA
B assay
Hereditary Familyhistoryofcirrhosis
hemochromatosis
Transferrinsaturationandplasmaferritinshouldbeperformedbutmaybe
elevatedbyliverdiseaseitself
Diagnosisestablishedbygenetictestingorliverbiopsyandcalculationof
hepaticironindex
Wilsondisease Familyorpersonalhistoryofcirrhosisatayoungage
Serumceruloplasminreducedin95percentofpatients
Liverbiopsyshowsincreasedcoppercontent,whichmayalsobeseenin
cholestaticliverdiseases
Alpha1 Familyorpersonalhistoryofcirrhosisatayoungage
antitrypsin
SerumAATphenotypingifloworborderlinevalues
deficiency
Nonalcoholicfatty Historyofdiabetesmellitusormetabolicsyndrome
liverdisease
Diagnosismaybesuspectedbyabnormalliverbiochemicaltestsandhepatic
imagingshowingfattyinfiltrationandisconfirmedbyliverbiopsy
Congestive Historyofrightsidedheartfailure,constrictivepericarditis,mitralstenosis,
hepatopathy tricuspidregurgitation,corpulmonale,cardiomyopathy
RightupperquadrantultrasonographywithDopplerstudiesoftheportaland
hepaticveinsandhepaticartery,electrocardiogram,andcardiacultrasound
AAT:alpha1antitrypsinANCA:antineutrophilcytoplasmicantibodyantiLKM1:antiliverkidney
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microsomal1antibodiesALT:alanineaminotransferaseAST:aspartateaminotransferaseDNA:
deoxyribonucleicacidELISA:enzymelinkedimmunosorbentassayHBeAg:hepatitisBeantigen
HBsAg:hepatitisBsurfaceantigenHBV:hepatitisBvirusHCV:hepatitisCvirusIg:immunoglobulin
PCR:polymerasechainreactionRNA:ribonucleicacid.
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ContributorDisclosures
NamitaRoyChowdhury,PhDNothingtodisclose.JayantaRoyChowdhury,MD,MRCPNothingtodisclose.
SanjivChopra,MD,MACPNothingtodisclose.AnneCTravis,MD,MSc,FACG,AGAFEquity
Ownership/StockOptions:Proctor&Gamble[Pepticulcerdisease/GIbleeding(omeprazole)].
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovided
tosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDate
standardsofevidence.
Conflictofinterestpolicy
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