Jaundice in the Adult Patient

SEAN P. ROCHE, M.D., Albany Medical College, Albany, New York

REBECCA KOBOS, M.D., University of Nevada School of Medicine, Reno, Nevada
Am Fam Physician.2004Jan15;69(2):299-304.

Jaundice in an adult patient can be caused by a wide variety of benign or life-threatening

disorders. Organizing the differential diagnosis by prehepatic, intrahepatic, and
posthepatic causes may help make the work-up more manageable. Prehepatic causes of
jaundice include hemolysis and hematoma resorption, which lead to elevated levels of
unconjugated (indirect) bilirubin. Intrahepatic disorders can lead to unconjugated or
conjugated hyperbilirubinemia. The conjugated (direct) bilirubin level is often elevated by
alcohol, infectious hepatitis, drug reactions, and autoimmune disorders. Posthepatic
disorders also can cause conjugated hyperbilirubinemia. Gallstone formation is the most
common and benign posthepatic process that causes jaundice; however, the differential
diagnosis also includes serious conditions such as biliary tract infection, pancreatitis, and
malignancies. The laboratory work-up should begin with a urine test for bilirubin, which
indicates that conjugated hyperbilirubinemia is present. If the complete blood count and
initial tests for liver function and infectious hepatitis are unrevealing, the work-up typically
proceeds to abdominal imaging by ultrasonography or computed tomographic scanning.
In a few instances, more invasive procedures such as cholangiography or liver biopsy
may be needed to arrive at a diagnosis.

ThewordjaundicecomesfromtheFrenchwordjaune,whichmeansyellow.Jaundiceisa
yellowishstainingoftheskin,sclera,andmucousmembranesbybilirubin,ayelloworangebile
pigment.Bilirubinisformedbyabreakdownproductofhemerings,usuallyfrommetabolized
redbloodcells.Thediscolorationtypicallyisdetectedclinicallyoncetheserumbilirubinlevel
risesabove3mgperdL(51.3perL).
Jaundiceisnotacommonpresentingcomplaintinadults.Whenpresent,itmayindicateaserious
problem.Thisarticlediscussestheevaluationoftheadultpatientwithjaundice.Asystematic
approachiswarrantedtoclarifythecausequicklysothattreatmentcanbeginassoonaspossible.

Pathophysiology
Theclassicdefinitionofjaundiceisaserumbilirubinlevelgreaterthan2.5to3mgperdL(42.8
to51.3perL)inconjunctionwithaclinicalpictureofyellowskinandsclera.Bilirubin
metabolismtakesplaceinthreephasesprehepatic,intrahepatic,andposthepatic.Dysfunctionin
anyofthesephasesmayleadtojaundice.

PREHEPATIC PHASE

Thehumanbodyproducesabout4mgperkgofbilirubinperdayfromthemetabolismofheme.
Approximately80percentofthehememoietycomesfromcatabolismofredbloodcells,withthe
remaining20percentresultingfromineffectiveerythropoiesisandbreakdownofmuscle
myoglobinandcytochromes.Bilirubinistransportedfromtheplasmatotheliverforconjugation
andexcretion.1
INTRAHEPATIC PHASE

Unconjugatedbilirubinisinsolubleinwaterbutsolubleinfats.Therefore,itcaneasilycrossthe
bloodbrainbarrierorentertheplacenta.Inthehepatocyte,theunconjugatedbilirubinis
conjugatedwithasugarviatheenzymeglucuronosyltransferaseandisthensolubleinthe
aqueousbile.
POSTHEPATIC PHASE

Oncesolubleinbile,bilirubinistransportedthroughthebiliaryandcysticductstoenterthe
gallbladder,whereitisstored,oritpassesthroughVater'sampullatoentertheduodenum.Inside
theintestines,somebilirubinisexcretedinthestool,whiletherestismetabolizedbythegutflora
intourobilinogensandthenreabsorbed.Themajorityoftheurobilinogensarefilteredfromthe
bloodbythekidneyandexcretedintheurine.Asmallpercentageoftheurobilinogensare
reabsorbedintheintestinesandreexcretedintothebile.

Clinical Presentation of Jaundice

Patientswithjaundicemaypresentwithnosymptomsatall(i.e.,theconditionisfound
accidentally),ortheymaypresentwithalifethreateningcondition.Thewiderangeof
possibilitiesisbasedonthevarietyofunderlyingcausesandwhetherdiseaseonsetisquickor
slowmoving.
Patientspresentingwithacuteillness,whichisfrequentlycausedbyinfection,mayseekmedical
carebecauseoffever,chills,abdominalpain,andflulikesymptoms.Forthesepatients,the
changeinskincolormaynotbetheirgreatestconcern.
Patientswithnoninfectiousjaundicemaycomplainofweightlossorpruritus.Abdominalpainis
themostcommonpresentingsymptominpatientswithpancreaticorbiliarytractcancers. 2Even

somethingasnonspecificasdepressionmaybeapresentingcomplaintinpatientswithchronic
infectioushepatitisandinthosewithahistoryofalcoholism. 3,4
Occasionally,patientsmaypresentwithjaundiceandsomeextrahepaticmanifestationsofliver
disease.Examplesincludepatientswithchronichepatitisandpyodermagangrenosum,and
patientswithacutehepatitisBorCandpolyarthralgias. 57
TABLE 1

Intrahepatic Causes of Conjugated Hyperbilirubinemia

Hepatocellular disease
Viral infections (hepatitis A, B, and C)
Chronic alcohol use
Autoimmune disorders
Drugs
Pregnancy
Parenteral nutrition
Sarcoidosis
Dubin-Johnson syndrome
Rotor's syndrome
Primary biliary cirrhosis
Primary sclerosing cholangitis

Adapted with permission from Pasha TM, Lindor KD. Diagnosis and therapy of cholestatic liver disease.
Med Clin North Am 1996;80:996.

Differential Diagnosis

Jaundicecanbecausedbyamalfunctioninanyofthethreephasesofbilirubin
production(Tables1and2).8Pseudojaundicecanoccurwithexcessiveingestionoffoodsrichin
betacarotene(e.g.,squash,melons,andcarrots).Unliketruejaundice,carotenemiadoesnot
resultinscleralicterusorelevationofthebilirubinlevel. 8
PREHEPATIC CAUSES

Unconjugatedhyperbilirubinemiaresultsfromaderailmentofthenecessarybilirubinconjugation
inthehepatocyte.Thisproblemmayoccurbeforebilirubinhasenteredthehepatocyteorwithin
thelivercell.Excessivehememetabolism,fromhemolysisorreabsorptionofalargehematoma,
resultsinsignificantincreasesinbilirubin,whichmayoverwhelmtheconjugationprocessand
leadtoastateofunconjugatedhyperbilirubinemia. 10
Hemolyticanemiasusuallyresultinmildbilirubinelevation,toabout5mgperdL(85.5molper
L),withorwithoutclinicaljaundice.Hemolyticanemiasresultfromabnormalredbloodcell
survivaltimes.Theseanemiasmayoccurbecauseofmembraneabnormalities(e.g.,hereditary
spherocytosis)orenzymeabnormalities(e.g.,glucose6phosphatedehydrogenasedeficiency).
Otheretiologiesofhemolysisincludeautoimmunedisorders,drugs,anddefectsinhemoglobin
structuresuchassicklecelldiseaseandthethalassemias. 11
INTRAHEPATIC CAUSES

Unconjugated Hyperbilirubinemia

Severaldisordersofenzymemetabolismaffecttheconjugationprocessinsidethehepatocyte,
therebyimpedingcompleteconjugation.Therearevaryingdegreesofunconjugated
hyperbilirubinemia,dependingontheseverityofenzymeinhibitionwitheachdisease.
TABLE 2

Extrahepatic Causes of Conjugated Hyperbilirubinemia

Intrinsic to the ductal system

Gallstones
Surgical strictures
Infection (cytomegalovirus, Cryptosporidium infection in patients with acquired immunodeficiency

syndrome)
Intrahepatic malignancy
Cholangiocarcinoma
Extrinsic to the ductal system
Extrahepatic malignancy (pancreas, lymphoma)
Pancreatitis

Adapted with permission from Pasha TM, Lindor KD. Diagnosis and therapy of cholestatic liver disease.
Med Clin North Am 1996;80:996.

Gilbertsyndromeisacommon,benign,hereditarydisorderthataffectsapproximately5percent
oftheU.S.population.1Typically,thediseaseresultsinamilddecreaseintheactivityofthe
enzymeglucuronosyltransferase,causinganincreaseintheindirectfractionofserumbilirubin.
Gilbertsyndromeistypicallyanincidentalfindingonroutineliverfunctiontests,whenthe
bilirubinlevelisslightlyincreasedandallotherliverfunctionvaluesarewithinnormallimits.
Jaundiceandfurtherelevationofthebilirubinlevelmayoccurduringperiodsofstress,fasting,or
illness.However,thesechangesareusuallytransient,andthereisnoneedtopursuetreatmentor
liverbiopsy.1
Conjugated Hyperbilirubinemia

Thepredominantcausesofconjugatedhyperbilirubinemiaareintrahepaticcholestasisand
extrahepaticobstructionofthebiliarytract,withthelatterpreventingbilirubinfrommovinginto
theintestines.
Viruses,alcohol,andautoimmunedisordersarethemostcommoncausesofhepatitis.
Intrahepaticinflammationdisruptstransportofconjugatedbilirubinandcausesjaundice.
HepatitisAisusuallyaselflimitedillnessthatpresentswithacuteonsetofjaundice.HepatitisB
andCinfectionsoftendonotcausejaundiceduringtheinitialphasesbutcanleadtoprogressive
jaundicewhenchronicinfectionhasprogressedtolivercirrhosis.EpsteinBarrvirusinfection

(infectiousmononucleosis)occasionallycausestransienthepatitisandjaundicethatresolveasthe
illnessclears.1,8
Alcoholhasbeenshowntoaffectbileaciduptakeandsecretion,resultingincholestasis.Chronic
alcoholusemayresultinfattyliver(steatosis),hepatitis,andcirrhosis,withvaryinglevelsof
jaundice.Fattyliver,themostcommonpathologicliverfinding,usuallyresultsinmildsymptoms
withoutjaundicebutoccasionallyprogressestocirrhosis.Hepatitissecondarytoalcoholuse
typicallypresentswithacuteonsetofjaundiceandmoreseveresymptoms.Livercellnecrosisis
indicatedbyhighlyelevatedserumlivertransaminaselevels. 12
Autoimmunehepatitistraditionallyhasbeenconsideredadiseasethataffectsyoungerpersons,
especiallywomen.Recentdata,however,supporttheconsiderationofthisdiagnosisinolder
patientswhopresentwithacuteicterichepatitis. 13Twoseriousautoimmunediseasesthatdirectly
affectthebiliarysystemwithoutcausingmuchhepatitisareprimarybiliarycirrhosisandprimary
sclerosingcholangitis.Primarybiliarycirrhosisisarareprogressiveliverdiseasethattypically
presentsinmiddleagedwomen.Fatigueandpruritusarecommoninitialcomplaints,while
jaundiceisalaterfinding.Primarysclerosingcholangitis,anotherrarecholestaticentity,ismore
commoninmen;nearly70percentofpatientsalsohaveinflammatoryboweldisease.Primary
sclerosingcholangitismayleadtocholangiocarcinoma. 8
DubinJohnsonsyndromeandRotor'ssyndromearerarehereditarymetabolicdefectsthatdisrupt
transportofconjugatedbilirubinfromthehepatocyte. 8
Manydrugshavebeenshowntoplayaroleinthedevelopmentofcholestaticjaundice.Agents
classicallyidentifiedwithdruginducedliverdiseaseareacetaminophen,penicillins,oral
contraceptives,chlorpromazine(Thorazine),andestrogenicoranabolicsteroids.Cholestasiscan
developduringthefirstfewmonthsoforalcontraceptiveuseandmayresultinjaundice. 14
POSTHEPATIC CAUSES

Conjugatedhyperbilirubinemiaalsomayresultfromproblemsthatoccurafterthebilirubinis
conjugatedintheliver.Theseposthepaticcausescanbedividedintointrinsicorextrinsic
obstructionoftheductsystem(Table2).8

Cholelithiasis,orthepresenceofgallstonesinthegallbladder,isarelativelycommonfindingin
adultpatients,withorwithoutsymptomsofobstruction.15Obstructionwithinthebiliaryduct
systemmayleadtocholecystitis,orinflammationofthegallbladder,aswellascholangitisor
infection.Cholangitisisdiagnosedclinicallybytheclassicsymptomsoffever,pain,and
jaundice,knownasCharcot'striad.Cholangitismostcommonlyoccursbecauseofanimpacted
gallstone.16
Impactedgallstonestypicallyrequirecholecystectomyorendoscopicremoval,dependingonthe
stonelocation.Biliarystricturesandinfectionshouldbeconsideredinpatientswithpostoperative
jaundice.10,16
Biliarytracttumorsareuncommonbutseriouscausesofposthepaticjaundice.Gallbladder
cancerclassicallypresentswithjaundice,hepatomegaly,andamassintherightupperquadrant
(Courvoisier'ssign).Survivalrates,basedontumorstage,rangefrom2to85percent.Another
biliarysystemcancer,cholangiocarcinoma,typicallymanifestsasjaundice,pruritus,weightloss,
andabdominalpain.Itaccountsforroughly25percentofhepatobiliarycancersandisassociated
withanapproximately50percentsurvivalrate. 16
Jaundicealsomayarisesecondarytopancreatitis.Themostcommoncausesofpancreatitisare
gallstonesandalcoholuse.Gallstonesareresponsibleformorethanonehalfofcasesofacute
pancreatitis,whichiscausedbyobstructionofthecommonductthatdrainsthebiliaryand
pancreaticsystems.15Evenwithoutductobstructionfromastone,pancreatitiscanleadto
secondarybileductcompressionfrompancreaticedema. 12

Physical Examination
Thephysicalexaminationshouldfocusprimarilyonsignsofliverdiseaseotherthanjaundice,
includingbruising,spiderangiomas,gynecomastia,testicularatrophy,andpalmarerythema.An
abdominalexaminationtoassessliversizeandtendernessisimportant.Thepresenceorabsence
ofascitesalsoshouldbenoted.

Evaluation

Theinitialworkupofthepatientwithjaundicedependsonwhetherthehyperbilirubinemiais
conjugated(direct)orunconjugated(indirect).Aurinalysisthatispositiveforbilirubinindicates
thepresenceofconjugatedbilirubinemia.Conjugatedbilirubiniswatersolubleandthereforeable
tobeexcretedinurine.Thefindingsofurinalysisshouldbeconfirmedbymeasurementsofthe
serumtotalanddirectbilirubinlevels(Figure1).
SERUM TESTING

Firstlineserumtestinginapatientpresentingwithjaundiceshouldincludeacompleteblood
count(CBC)anddeterminationofbilirubin(totalanddirectfractions),aspartatetransaminase
(AST),alaninetransaminase(ALT),glutamyltranspeptidase,andalkalinephosphataselevels.
ACBCisusefulindetectinghemolysis,whichisindicatedbythepresenceoffracturedredblood
cells(schistocytes)andincreasedreticulocytesonthesmear.
ASTandALTaremarkersofhepatocellularinjury.Theycanbelesshelpfulinpatientswith
chronicliverdisease,becauselevelscanbenormaloronlyslightlyelevatedwhenthereislittle
liverparenchymalefttodamage.AcuteviralhepatitismaycausethelevelsofALTtoriseseveral
thousandunitsperliter.Levelsgreaterthan10,000UperLusuallyoccurinpatientswithacute
injurytotheliverfromanothersource(e.g.,drugs[acetaminophen]orischemia). 17
PatientswithacutealcoholichepatitishaveASTandALTlevelsthatrisetoseveralhundredunits
perliter.Withalcoholinduceddamage,theratioofASTtoALTisusuallygreaterthan1,
whereasinfectiouscausesofhepatitistypicallycausegreaterelevationinALTthaninAST. 18
Alkalinephosphataseandglutamyltransferasearemarkersforcholestasis.Asbileobstruction
progresses,thelevelsofthesetwomarkersriseseveraltimesabovenormal. 17
Dependingontheresultsoftheinitialtests,furtherserumtestsorimagingstudiesmaybe
warranted.ThesecondlineseruminvestigationsmayincludetestsforhepatitisAIgMantibody,
hepatitisBsurfaceantigenandcoreantibody,hepatitisCantibody,andautoimmunemarkers
suchasantinuclear,smoothmuscle,andliverkidneymicrosomalantibodies.Anelevated
amylaselevelwouldcorroboratethepresenceofpancreatitiswhenthisconditionissuspected
basedonthehistoryorphysicalexamination.

Clinical Jaundice in Adults

FIGURE 1.
Algorithm for a systematic approach to the adult patient with jaundice. (AST = aspartate transaminase; ALT
= alanine transaminase; AP = alkaline phosphatase; GGT = -glutamyltransferase; CBC = complete blood
count; ANA = antinuclear antibodies; anti-LKM = liver-kidney microsomal antibodies; US = ultrasonography;
CT = computed tomography)
IMAGING

Ultrasonographyandcomputedtomographic(CT)scanningareusefulindistinguishingan
obstructinglesionfromhepatocellulardiseaseintheevaluationofajaundicedpatient.
Ultrasonographyistypicallythefirsttestordered,becauseofitslowercost,wideavailability,and
lackofradiationexposure,whichmaybeparticularlyimportantinpregnantpatients.While
ultrasonographyisthemostsensitiveimagingtechniquefordetectingbiliarystones,CTscanning
canprovidemoreinformationaboutliverandpancreaticparenchymaldisease.Neithermodality
isgoodatdelineatingintraductalstones.19
Furtherimagingthatmaybedonebyagastroenterologistorinterventionalradiologistincludes
endoscopicretrogradecholangiopancreatographyandpercutaneoustranshepaticcholangiography.
LIVER BIOPSY

Aliverbiopsyprovidesinformationonthearchitectureoftheliverandisusedmostlyfor
determiningprognosis.Italsomaybeusefulfordiagnosisifserumandimagingstudiesdonot
leadtoafirmdiagnosis.Liverbiopsycanbeparticularlyhelpfulindiagnosingautoimmune
hepatitisorbiliarytractdisorders(e.g.,primarybiliarycirrhosis,primarysclerosingcholangitis).
Patientswithprimarybiliarycirrhosisarealmostalwayspositiveforantimitochondrialantibody,
andthemajorityofthoseaffectedbyprimarysclerosingcholangitishaveantineutrophil
cytoplasmicantibodies.8
Theriskoffatalhemorrhageinpatientsundergoingpercutaneousliverbiopsyis0.4percentif
theyhaveamalignancyand0.04percentiftheyhavenonmalignantdisease. 20

The Authors
SEAN P. ROCHE, M.D., is assistant professor of family and community medicine at Albany (N.Y.) Medical
College and associate director of the family practice residency program at Albany Medical Center. Dr. Roche

received his medical degree from the State University of New York (SUNY) Upstate Medical University,
Syracuse. He completed a family medicine residency and served as chief resident at Albany Medical Center.
REBECCA KOBOS, M.D., is assistant professor of family and community medicine at the University of
Nevada School of Medicine, Reno. Dr. Kobos received her medical degree from SUNY Upstate Medical
University. She completed a family medicine residency at Albany Medical Center, where she served as chief
resident.
Address correspondence to Sean P. Roche, M.D., Department of Family and Community Medicine, Albany
Medical College, 2 Clara Barton Dr., Albany, NY 12208. Reprints are not available from the authors.