Rev. Bras. Hematol. Hemoter. vol.39 número2

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revbrashematolhemoter.2017;39(2):163–166

w w w . r b h h . o r g

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Case

Report

Sickle

cell

intrahepatic

cholestasis

unresponsive

to

exchange

blood

transfusion:

a

case

report

Juliana

Albano

de

Guimarães,

Luciana

Cristina

dos

Santos

Silva

∗

UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil

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l

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o

Articlehistory:

Received7September2016 Accepted15February2017 Availableonline11March2017

Introduction

Sickle cell intrahepatic cholestasis (SCIC) is an uncom-mon but severe complication in sickle cell disease (SCD) patients homozygous for hemoglobin (Hb) S or with Hb S/␤ thalassemia.1–3 _It_is _clinically_{characterized} _by_marked

conjugated hyperbilirubinemia, right upper quadrant pain, enlargedliverandmoderatelyelevatedhepaticenzymes.In moreseverecases,coagulopathyandrenaldysfunctionmay be observed and the condition occasionally progresses to liverfailure.SCIC ismostcommonlydescribed initsacute or recurrentforms but it eventually becomes chronic. The pathogenesisofSCICinvolvessicklingwithinthehepatic sinu-soids leadingto vascular stasis,hypoxiaand ballooning of thehepatocytes,resultinginintracanalicularcholesthasis.1,4

Treatmentisbasedonexchangebloodtransfusions(EBT)and aimstoreduceHbSbloodlevelsandconsequentlythesickling process.AlthoughseveralcasereportsshowreversalofSCIC withpromptEBT,1,3,5_we_describe_a_case_of_a_{non-responsive}

patientwhoperisheddespitetreatment.

∗ _{Corresponding}_author_at_:_Internal_Medicine_Department,_Universidade_Federal_de_Minas_Gerais_(UFMG),_Av._Prof._Alfredo_Balena,_190, Sala246,BeloHorizonte,MG,CEP:30130-100,Brazil.

E-mailaddress:[email protected](L.C.Silva).

Case

report

Thepatientwasa38-year-oldAfro-BrazilianwomanwithSCD (HbSS)andamedicalhistoryofcomplicationsofherdisease: acutepainfulvaso-occlusivecrises,boneinfarcts,skinulcerof thelowerlimb,acutechestsyndromeandautosplenectomy. Shehadnohistoryofalcoholabuseandhadanormalbody massindex.Shecomplainedofjaundice,choluria,dyspnea onlightexertionandpainintherightupperabdominal quad-rantandinthelowerlimbsthatstartedfourmonthspriorto hospitaladmission.

Thephysicalexaminationathospitaladmissionrevealeda patientindistress,presentingabloodpressureof140×90mm Hg,heartrateof81beatsperminute,respiratoryrateof18 breathsperminute,temperatureof36.7◦_C,_and_oxygen

satu-rationof96%.Respiratorysoundswerenormalandapainful enlargedliverwasidentified.

Laboratory tests showed anemia (Hb: 6.7g/dL; hema-tocrit: 21%) and cholestasis (total bilirubin: 16.01mg/dL; directbilirubin: 12.11mg/dL)withaslightelevationofliver

http://dx.doi.org/10.1016/j.bjhh.2017.02.006

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enzymes[aspartateaminotransferase(AST):138U/L;alanine aminotransferase (ALT): 46U/L; alkaline phosphatase (ALP) 445U/L;gamma-glutamyltransferase(GGT)437mg/dL]. Albu-minlevelswereatthelowernormallimit(3.4g/dL)andthe international normalizedratio (INR) was atthe upper nor-mal limit (1.37). Serology tests for hepatitis B and C, HIV and autoimmune conditions were negative. She had pos-itive immunoglobulin (Ig)G antibodies for cytomegalovirus and Epstein–Barr virus. Alpha-fetoprotein and ceruloplas-min were within the normal ranges and iron metabolism markerswereslightlyaltered(iron:174␮g/dL;transferrin sat-uration:68%;totalironbindingcapacity:256␮g/dL;ferritin: 575ng/dL).Inaddition,renalfunctionwaspreserved (creati-nine:0.53mg/dL),bloodcultureswerenegativeandchestX-ray revealednochangeofthepulmonaryparenchyma.TheHbS fractiononemonthbeforehadbeen74%.

Magneticresonanceimaging(MRI)oftheabdomenshowed an enlarged liver withslightly irregular contours and het-erogeneousparenchymasuggestiveofchronicliverdisease, associatedwithsmall volumeascites (Figure1A). Gallblad-derandcholedocusductweretypicalatmagneticresonance cholangiopancreatography (MRCP).Therewas aslightfocal dilatationofthebiliarytreeintherighthepaticlobe,butno biliaryobstructionwasdetected(Figure1B).

Thepatientwasgivenintravenousfluids,analgesia,folate andsupplementaryoxygen therapy.Shereceived900mLof packedredbloodcellsinordertoincreasethehematocritto 25%,followedbyEBT.Transfusionsledtoclinicalimprovement andtheHbSfractiondroppedto14.3–20.4%.Despite resolu-tionofrespiratorydistressandlowerlimbpain,shepersisted withjaundice,choluriaandaslightabdominalpain.

On the 13th day of hospitalization, she presented with acuterespiratorydistress,associatedwithfeverand hypox-emia.AchestX-rayrevealeddiffuselungopacities andthe diagnosisofacutechestsyndromewasreached.Thepatient was transferredtothe intensive careunit (ICU),placedon mechanical ventilation and meropenem therapy was initi-ated.Shepresentedmentalconfusionandanisolatedseizure. Herclinicalconditionandcomputed tomography(CT) find-ingssuggestedposteriorreversibleencephalopathysyndrome (PRES). Normal levels of ammonia discarded the hypothe-sis of hepatic encephalopathy. She gradually evolved with increasinglevelsofdirectbilirubinandelevatedINR,despite maintenanceof Hb S below25%. Figure 2 shows the evo-lutionofalbumin, hemoglobin,INR,bilirubin, ASTandALT duringhospitalization.Renalfunctionprogressively deterio-ratedoverherlastsixdaysoflife,reachingacreatininelevelof 3.31mg/dLonthedayofherdeath.Bloodandairwaysecretion culturescollectedintheICUwerenegative.Onthe32ndday ofhospitalization,sheevolvedwithrefractoryshockresulting indeath.

Discussion

DiagnosisofSCICisbasedonclinicalandlaboratoryevidence ofnon-obstructivecholestasis, moderatelyelevatedhepatic enzymes and an enlarged and painful liver. The patient describedinthisreportshowedallthecharacteristicfeatures of SCIC, including marked conjugated hyperbilirubinemia,

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Figure1–(A)AxialT2weightedmagneticresonance imagingoftheabdomenshowingliverenlargementwith increasedleft(LL)andcaudate(CL)lobes,associatedto slightlyirregularcontours(arrows).(B)Magneticresonance cholangiopancreatographyshowingnormalgallbladder andslightfocaldilatationofthebiliarytree(arrows)inthe righthepaticlobewithoutbiliaryobstruction.

rightupperquadrantpain,enlargedliver,andacoagulation disorder,butonlymoderatelyelevatedliverenzymes. Accord-ing toAhn etal., SCIC can besubdivided asmild(average directbilirubin27.6mg/dL)andseverediseases(averagedirect bilirubin76.8mg/dLorpresenceofchangeinmentalstatus orcoagulationdisorder),withthedeathratesbeing4%and 64%,respectively.5_Our_patient_fit_the_criteria_of_severe_disease

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Figure2–(A)Evolutionofalbumin(g/dL),hemoglobin(g/dL)andinternationalnormalizedratio(INR)duringhospitalization. (B)Evolutionofdirectandindirectbilirubinlevels(mg/dL),aspartateaminotransferase(AST-U/L)andalanine

aminotransferase(ALT-U/L)duringhospitalization.Narrowarrowsrefertoredbloodcelltransfusionsandthewidearrow indicatesexchangebloodtransfusion(EBT).

MRIquantificationofhepaticironconcentrationwasnot per-formed,buthemochromatosiswasunlikely.Despitehistoryof complicationsofherdisease,previousmultipletransfusions werenotreportedandironmetabolismmarkerswerejusta lit-tlechanged.Theferritinlevel,althoughhigh(575ng/dL),has lowspecificityandcanbehighinbothliverand inflamma-torydiseases.Furthermore,thepatientdidnotreportusing anyhepatotoxicsubstance.Liverbiopsywasnotcarriedout, sincethis procedureinvolveshighmorbidityandmortality, particularlyinthepresenceofanacutehepaticlesion.4,6,7

Regardingtreatment,therearenorandomizedclinical tri-alswithsufficientevidencetoproveefficacyoftherapeutic measures.8_However,_the_prognosis_of_SCIC_improved

signifi-cantlywiththeadventofEBT.Ahnetal.showedthatsevenout ofninepatientswithsevereSCICwhoreceivedEBTsurvived,

while12of13patientsnotundergoingEBTdied.5_Hb_S_fraction

levelsbelow20–30%wereestablishedasideal,butagainthere islackofevidence,withonlypragmatisminrelationtothese values.1–5_There_is_evidence_that_{ursodeoxycholic}_acid_protects

againstthecytotoxicityandapoptosisinducedbyhydrophobic bileacids.Itisatherapeutictoolinprimarybiliarycirrhosis, sclerosingcholangitis,intrahepaticcholestasisofpregnancy, cystic fibrosis, progressive familial intrahepatic cholestasis andchronicgraft-versus-hostdisease.9 _Some_authors_claim

thatitcouldimprovebiliaryflowinSCIC,4_but_its_use_has_not

yetbeenestablishedinthiscondition.8

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20.4%indifferentmeasures),therewasdeteriorationinthe clinicalcourseofSCIC.Startingtreatmentwiththedisease alreadyin anadvanced stagemay havecontributed tothe bad outcome inthis case. Thelackofresponse could also beduetotheconcomitanceofanotherundiagnosedhepatic disease.Althoughbloodandairwaysecretioncultureswere negative,thepatientprobablydevelopedsepsis,whichcould havecontributedtocholestasis,liverdysfunctionanddeath.7

Additionally,acutechestsyndromeclearlyinfluencedclinical deteriorationandfataloutcome.

Berryetal.described38patientswithsicklecell hepatopa-thy,varyingfromself-limitedcholestasistoacuteliverfailure and cirrhosis.7 _The_authors _reported _55% _mortality_among

patientswithacutepresentationsofhepaticdisease,requiring emergency admission. All four cirrhotic patients admit-ted with acute hepatic decompensation died. The patient describedhereinhadnoclinical signsofcirrhosisorportal hypertension.LaboratorytestsrevealedalbuminandINRto bewithinthelimitsofnormality,whileMRIshowedsignsof chronicliverdisease.Nevertheless,wedecidednottoperform abiopsytodiscardsuchancondition, asthisprocedure in hersevereacuteconditioniscorrelatedtohighmortalityand complicationssuchasbleeding.4,6,7_Costa_et_al._reported_a_case

ofSCICunresponsivetoEBTinwhichthe48-year-oldpatient hadcirrhosiswithoutmajorclinicalchangesasidentifiedby liverbiopsybut hadahistory ofhepatitisCvirus infection withthe viralload being undetectableforyears beforethe cholestasis.Themainhypothesisabouttheunfavorable out-comewasrelatedtoalesseffectiveresponsetoEBTinolder patientsand/orthepresenceofotherliverconditionssuchas cirrhosis.2_Gardner_et_al._described_a_27-year-old_patient_with

SCICwhowassuccessfullysubmittedtolivertransplantation andtheauthorssuggestedthatthisprocedureisanalternative treatmentinspecialcases.4

Finally,itisknownthatthesicklingprocessdependsnot onlyon the percentageof Hb S but also on inflammatory events,suchasthoserelatedtoinfection,thatoftentriggerHb Spolymerization.Thisresultsfromthedynamicinteraction betweenthecellsandthevascularendotheliumwith subse-quenttissuedamageresultingfromischemiaand oxidative stress.Thesubsequentinflammatorystatuswithincreased expressionofendothelialadhesionmoleculesandcytokines couldtriggersicklinginthemicrovasculatureand perpetua-tionofSCIC.10

Inconclusion,itisveryimportanttorecognizeintrahepatic cholestasis,anuncommonbutseverecomplicationofsickle celldisease.Effortstoelucidatethephysiopathological mech-anismsinvolvedinthis processare needed.AlthoughEBTs seemtobethemosteffectivetreatmentforsicklecell intra-hepatic cholestasis,studiesarestillnecessarytodefinethe besttherapeuticapproachandtoidentifyfactorsassociated toclinicaloutcomes.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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