TurkJMedSci 34(2004)275-279 ©TÜB‹TAK SHORT REPORT AcuteHepaticFailureinaCaseofAcuteLymphoblasticLeukemia SalihCESUR1,PervinTOPÇUO⁄LU2,OzanAfiIK3,SerhatB‹RENGEL3 ,MuhitÖZCAN2 1 RefikSaydamHygieneCenterTuberculosisReferenceLaboratory,Ankara-Turkey 2 DepartmentofHematology,FacultyofMedicine,AnkaraUniversity,Ankara-Turkey 3 DepartmentofInfectiousDiseasesandClinicalBacteriology,FacultyofMedicine,AnkaraUniversity,Ankara-Turkey Received:September22,2003 KeyWords: Hepaticfailure,leukemicinfiltration,liver,acutelymphoblasticleukemia Hepatomegalyandmildelevationofserum historyrevealedthatoneofhissiblingshad transaminasevaluesthatmightbecausedbyinfiltration neurofibromatosis,thepatienthadnottakenanytoxic ofleukemiccellsareseeninsomecasesofleukemia.It drugandnojaundicecasewaspresentinhisfamily.The mayresultfromsuchconditionsasviralhepatitis,liver patientwasgenerallywell,alertandnotconfused.His toxicityduetochemotherapyandleukemicliver temperaturewas37.9°Candpulse88/min.Therewasa infiltration.However,severejaundiceisrarelyobserved, markedicterusinthescleraandtheskin.Hehadno especiallyattheonsetofleukemiaanditgreatly splenomegalyorhepatomegaly.Laboratoryinvestigations complicatesinitialtherapybecausemostinductionagents showedthattheleukocytecountwas2500/mm 3,Hb aremetabolizedprimarilybytheliver.Manyauthorshave 14.1g/dl,platelet80,000/mm 3 anderythrocyte reportedadultpatientswithmalignanciespresentingwith sedimentationrate10mm/h.Biochemicalanalysis fulminanthepaticfailure(1-2).Zafranietal.(3)reported demonstratedthattotalbilirubinwas18.9g/dl,direct 4adultswithacutemonoblasticleukemia,acutephaseof bilirubin10.3g/dl,AST350U/L,ALT1140U/LandLDH chronicmyelogenousleukemia,orlymphomapresenting 1789U/L.Otherbiochemicaltestswerenormal.The withfulminanthepaticfailure.Harrisonetal.(4) hepatitismarkersanti-HBsandanti-HAVIgGwere reported3patientswithmetastaticliverdiseasewho positivebutHBsAg,anti-HCVandanti-HAVIgMwere presentedwithaclinicalcoursecompatiblewithfulminant negative.PolymerasechainreactionshowedthatHBV- hepaticfailure.Severehepatocellulardysfunctionhasalso DNAandHCV-RNAwerenegative.Otherviralmarkers beenreportedinassociationwithextensivemetastatic includingEBVIgM,CMVIgM,HSV-IandIIIgMandHPV- liverdisease.Whenpublicationswerereviewedand B19werenegativebut,EBVIgG,CMVIgGandHSV-Iand analyzedfromPubmed,wefoundanectodalcasereports IIIgGwerepositive.Peripheralbloodfilmshowed presentingliverdysfunctionandleukemiashowinga atypicallymphocytes,blastcellsandneutropenia(Figure spontaneousimprovement.Wereportacutehepatic 1).Becausehisbodytemperatureexceeded38.3°C,an failureinacaseofacutelymphoblasticleukemia. empiricdoubleantibioticcombinationconsistingof sefepimandamicacinewereinitiatedtotreathim accordingtothefebrileneutropeniaprotocol.To Case establishtheetiologyofthepancytopenia,thepatientwas A15year-oldboypresentedatourclinicwitha2 referredtothedepartmentofhematology.The weekshistoryofanorexia,malaiseandjaundiceinthe examinationsofperipheralbloodandbonemarrow scleraoftheeyeandskin,withdarkenedurine.The aspirationrevealedaleukemicinfitration.Escherichiacoli 275 AcuteHepaticFailureinaCaseofAcuteLymphoblasticLeukemia immunohistochemicalinvestigations.Cytogeneticanalyses detectedhypodiploidyandclonaldeletionofchromosome 22.RemissioninductionchemotherapyforALLwasnot initiatedinthepatientbecauseoftheriskofinducing massivelivernecrosisandaworseoutcome. Approximately1weeklater,hisclinicalandlaboratory parameterssuchasfever,completebloodcount,liver functiontestsandperipheralbloodsmearstartedto improvewithsupportivecareandempirical antibiotherapyandhebecamealmostnormal.Atthis time,toclarifytheunexpectedimprovement,itwas decidedtorepeatthebonemarrowexaminationbuthis familydidnotgivepermissionforthisrepeatprocedure. Figure1. Patient’speripheralbloodfilmshowsatypicallymphocytes, Becauseofthisimprovementintheclinicalandlaboratory blastcellsandneutropenia. picture,wedecidedtofollowthepatientwithouttherapy. Afterseveraldays,thefeverrosetogetherwithsevere wasisolatedinperipheralbloodandbonemarrow jaundiceinthepatient.Thelaboratoryparameters cultures.Jaundicewasconsideredtobesecondaryto includingliverfunctiontestsandcompletebloodcount leukemicliverinfiltrationsinceothercausesofhepatitis rapidlydeteriorated(Figures2-4).Weobservedleukemic (i.e.viralhepatitis,toxichepatitis,andmetabolicliver cellsintheperipheralbloodsmearagain.Withinseveral disease)wereruledout.Thepatient’sabdominal days,theclinicalpicturerapidlyprogressedtohepatic ultrasonographicimagingshowedparanchymal failureandencephalopathy.Finally,hediedofmulti- echogenity,granulationpatternswithoutmassand organfailure.Nopostmortemexaminationwas hepatosteatosis.Atthistime,weplannedtoperforma performedsinceinformedconstentfromthepatient’s liverbiopsytoclarifythecauseofhepaticdysfunction. familycouldnotbeobtainedforautopsy. However,itwasnotperformedduetothelowlevelof plateletsandcoagulopathy.Inaddition,hisfamilydidnot Discussion givepermissionforthisprocedure.Thepatientwas definitelydiagnosedwithaberrantmyeloidmarker Hepaticinvolvementismostoftenmoderatein bearingpre-BALLconsequenttoflowcytometryand patientswithALL,chroniclymphocyticleukemia(CLL), 14 250 12 200 10 8 150 6 100 4 50 2 0 * * * * **** *** 0 0135811182027282930* Days Leukocyte(x109/L) Neutrophil(x109/L) * Hemoglobin(g/d) Platelet(x109/L) Figure2.Thecourseofcompletebloodcountfrominitialpresentationtodeath. 276 S.CESUR,P.TOPÇUO⁄LU,O.AfiIK,S.B‹RENGEL,M.ÖZCAN 7000 6000 6000 * 5000 5000 * 4000 4000 * 3000 IU/l 3000 * IU/l 2000 2000 * * * 1000 1000 * * 0 ***** 0 -1000 0 1 3 5 8111618202527282930-1000 Days AST(IU/L) ALT(IU/l) ALP(IU/l) GGT(IU/l)* LDH(IU/l) Figure3.Thecourseofliverenzymesfrominitialpresentationtodeath. 25 3.8 3.6 20 3.4 3.2 15 3 2.8 10 2.6 Serumbilirubin(g/d) 5 2.4 Serumalbumin(g/d) 2.2 0 2 0 1 3 5 8 11 16 18 20 25 27 28 29 30 Days T.bilirubin(g/d) D.bilirubin(g/d) Albumin(g/d) Figure4.Thecourseoftheserumlevelsofbilirubinandalbuminfrominitialpresentationtodeath. Hodgkin’sdisease(HD),non-Hodgkin’slymphomas(NHL) InpatientswithALL,significantenlargementoftheliver andtheblasticcrisisofchronicmyeloidleukemia(CML), waslinkedtoapoorprognosis.Evenincasesassociated butitisunusualinmultiplemyeloma(MM)patients. withmarkedhepatomegaly,liverfunctionabnormalities Hepatomegalymaybepresentatthetimeofdiagnosis areoftenmild.Ifanyhepaticdysfunctiondoesoccur,itis butonlyrarelydoesliverdysfunctiondominate(5). usuallyaccompaniedbyjaundice.Whilejaundicemaybe Pathologically,thelivershowsdiffuseenlargement duetoavarietyorcomplicationssuchasviralhepatitis, secondarytoinfiltrationbyleukemiclymphoblasts.InALL bacterialinfection,ortoxicityfromanti-tumortherapy,it andCLL,theinvolvementofperiportalspacesby mostoftenreflectsinfiltrationoftheliverbythetumor, neoplasticcellswascommon.Hepatomegalymayalsobe atleastinpatientswithHD.Accuratedifferentiationof theresultofhypertrophyofhepatocytesintheleukemias. thevariouscausesofjaundiceisimportant,butexceptfor 277 AcuteHepaticFailureinaCaseofAcuteLymphoblasticLeukemia distinguishingjaundiceduetohemolysisfromthatdueto sincetheliverbiopsycouldnotbeperformed.MostALL liverdisease,thisisoftenadifficulttask.Clinicalfeatures patientsinitiallypresentwithclinicalsymptomsresulting andliverfunctiontestsusuallyareoflittlehelpin frombonemarrowfailure.Onethirdhaveinfectionor differentiatingliverdiseaseduetotumorinvasionfrom feveratpresentation.Approximatelyonehalfofthe thatduetoothercauses.Alkalinephosphataseandleucine patientspresentedatdiagnosiswithlymphadenopathy, aminopeptidaseareoften,butnotinvariably,elevated splenomegalyandhepatomegaly(6).Therewererare withtumorinvasion.Liverbiopsycanbehelpfulandis reportsofspontaneousremissionsafterviralorbacterial indicatedunlesscoagulationisabnormalorposthepatic infectionsortransfusionsinacuteleukemia(10-12). biliaryobstructionissuspected(6).Scheimberetal. Cytogeneticanalysishasbecomecriticalforthe reportedhistopathologicalfindingsintheliverinaseries predictionofoutcomeandselectionoftherapyinALL. ofautopsieson110patientssufferingfromleukemiaand Clonalchromosomalalterationsarepresentin75%of lymphoma(7).Theyshowedthat10of25untreated cases.ThemajorcytogeneticabnormalitiesinALLare patientshadneoplasticinfiltration.Theclinicaland clonaltranslocations(t[9;22],t[4;11],t[8;14],t[1;19] pathologicalfindingsin4caseswithfulminanthepatic ort[10;14]andotherstructuralabnormalities(9p,6q, failureduetomassiveinfiltrationoftheliverbyacute or12pabnormalities)(6).Therewerehypodiploidyand leukemiaorlymphomahavebeenreported(6).Liver clonaldeletionofchromosome22incytogenetical abnormalitieswerefoundsimultaneouslywith,orledto analysisofthebonemarrowofourpatient.Hypodiploidy thediscoveryof,hematologicmalignanciesandconsisted wasasignofunfavorableprognosis.Althoughthe ofmarkedhepatomegalyandseverehepatocellular importanceofclonaldeletionofchromosome22is insufficiency.Immediatechemotherapywasinstitutedin unknown,thisabnormalitymightbeapartoft(9;22), thesecasesandcompleteremissionswithouthepatic withanunfavorableoutcome,usuallymissedonstandard complicationswereobtained.Itissuggestedthat cytogeneticanalysis.Weobservedmyeloidantigen malignanthematologicaldiseaseswithrapidcellular expressiononlymphoidblastcellsbytheflow growthmaypresentasfulminanthepaticfailure.Inorder cytometricalexamination.Thisfindingdoesnotappearto toavoidarapidlyfataloutcomesecondarytoliverfailure haveanyindependentprognosticsignificancebutmaybe andmetabolicdisorders,earlyrecognitionofthese anadverseprognosticfactorinadults(13). malignanciesisnecessarysoastoassureprompt administrationofappropriatechemotherapy(3). Inconclusion,ourcaseillustratesthatliver Systemicchemotherapyisthetreatmentofchoicefor