Fulminant Hepatitis E in a Pregnant Woman

www.elsevier.pt/ge

CLINICAL

CASE

Fulminant

hepatitis

E

in

a

pregnant

woman

Mónica

Velosa

_,

_António

_Figueiredo

_,

_Helena

_Glória

_,

_Ana

_Morbey

_,

Elia

Mateus

_,

_Zélia

_Neves

_,

_Ana

_Araújo

_,

_Ana

_Carvalho

_,

Judite

Oliveira

_,

_Eduardo

_Barroso

a_{Servic¸odeGastrenterologia,HospitalCentraldoFunchal,Funchal,Portugal} b_{UnidadedeTransplantac¸ão,HospitalLisboaCentral---CurryCabral,Lisboa,Portugal} c_{Servic¸odeAnatomiaPatológica,HospitalLisboaCentral---CurryCabral,Lisboa,Portugal} d_{UnidadedeCuidadosIntensivos,HospitalLisboaCentral---CurryCabral,Lisboa,Portugal}

Received17October2012;accepted29April2013 Availableonline5October2013

KEYWORDS

HepatitisEvirus; Livertransplant; Fulminanthepatitis; Pregnancy

Abstract HepatitisEisaninflammatoryliverdiseasecausedbyhepatitisEvirus(HEV) infec-tion,whichisendemicinChina,India,Nepal,andinseveralAsianandAfricancountries,where the prevalencecan be as highas 50%.In non-endemiccountries, an increasing number of non-travelassociatedHEVhasbeenreportedinrecentyears,particularlyinEurope.

Theauthorsdescribetheclinicalcaseofapuerperal24-year-oldwomanfromPakistan admit-tedtoourTertiaryCareMedicalCenterwithacutehepaticfailuredevelopedduringthethird trimesterofherpregnancy.ShewasictericwithgradeIIIencephalopathyandhypothermia. LaboratoryvaluesshowedsignificantAST,ALTandLDHelevationsoftwelvetimestheupper normallimit,andtotalbilirubinwassignificantlyelevated(41.20mg/dL).Prothrombintimewas prolonged(4s)andfactorV activitywasdiminished(15.1%). Extracorporealalbumindialysis wasinitiated,butclinicaldeteriorationoccurredwithin48h,sosheunderwentOLTatday4 post-admission.

SevereformsofHEVareknowntobemorepronouncedinpregnantwomen.Eventhough mostofthedescribedcasesofacutehepaticfailureassociatedtoHEVduringpregnancyhad afavorableclinicalcourse,somecasesoffulminantliverfailureanddeatharedescribed.Itis unknownwhetherlivertransplantoutcomesinthissettingaredifferentfromothercausesof acuteliverfailure.Toourknowledge,thisisthefirstcasereportinPortugalfromapregnant womanwhodevelopedhepaticfailureduetofulminanthepatitisEthatunderwentsuccessful livertransplantation.

©2012SociedadePortuguesadeGastrenterologiaPublishedbyElsevierEspaña,S.L.Allrights reserved.

∗_{Correspondingauthor.}

E-mailaddress:mo.velosa@gmail.com(M.Velosa).

0872-8178/$–seefrontmatter©2012SociedadePortuguesadeGastrenterologiaPublishedbyElsevierEspaña,S.L.Allrightsreserved. http://dx.doi.org/10.1016/j.jpg.2013.04.005

PALAVRAS-CHAVE

VírusdahepatiteE; Transplantehepático; HepatiteFulminante; Gravidez

HepatiteEfulminantenumamulhergrávida

Resumo AHepatiteEéumadoenc¸ainflamatóriadofígadocausadapeloVírusdaHepatiteE (VHE).EstevíruséendémiconaChina,Nepal,ÍndiaeemváriospaísesAfricanoseAsiáticos, onde asuaprevalência pode atingiros 50%.Em paísesnão endémicos, particularmente na Europa,tem-severificadoumaumentodaprevalênciadeVHEnãoassociadaaviagens.

Osautoresdescrevemocasodeuma doentede24 anos,puérpera,naturaldoPaquistão, admitida nonossoCentroTerciáriocominsuficiênciahepáticaaguda, cominícionoterceiro trimestre dagravidez.A doenteencontrava-se ictérica,comencefalopatia hepática grauIII ehipotermia.Osvaloreslaboratoriaismostraram elevac¸ãosignificativade12 vezesolimite superiordonormaldasaminotransferases(ASTeALT)edaLDH,combilirrubinatotalelevada (41.2mg/dL),prolongamentodotempodeprotrombina(4seg)eactividadedofactorV dimin-uída(15.1%).Adoenteinicioudiálisedealbuminaextra-corporal,contudoverificou-serápida deteriorac¸ão,tendosidosubmetidaatransplantehepáticono4◦diaapósaadmissão.

FormasmaisgravesdehepatiteassociadaaVEHtêmsidodescritasduranteagravidez. Geral-mente,mesmoasformasmaisgraves têmumaevoluc¸ãotendencionalmentefavorável,com apenasalgunscasosdescritosdemorteedehepatitefulminante.Desconhece-separajáqual oresultadoalongoprazodosdoentestransplantadosporhepatiteEfulminante,quando com-parados comoutraspopulac¸ões. Estecaso representaoprimeiro casodescritoem Portugal deumadoentegrávidacomhepatitefulminantecausadaporVHE,submetidacomsucessoa transplantehepático.

©2012SociedadePortuguesadeGastrenterologia.PublicadoporElsevierEspaña,S.L.Todosos direitosreservados.

Introduction

HepatitisEisaninflammatoryliverdiseasecausedby hep-atitis E virus (HEV) infection, which is a single-stranded, non-envelopedRNAvirusandtheonlyviruswithinthegenus

HepevirusandthefamilyHepeviridae.1,2_{Thefirstdescribed} casesofacuteliverdiseasecausedbyanentericinfectious agentthatdifferedfromhepatitisAandhepatitisBviruses were reported in India in the 1970s.2 _{HEV is endemic in} China,India,Nepal,aswellasinseveralAsianandAfrican countries,wheretheprevalenceofHEVIgGantibodycanbe ashighas50%.3_{Ithasbeenrecentlyestimatedthatits} infec-tioncausesmorethan3millionsymptomaticcasesofacute hepatitis E each year, resulting in approximately 70,000 deaths worldwide.4 _{In non-endemiccountries, an} increas-ingnumber ofnon-travel associated HEVcaseshave been reportedinrecentyears,particularlyinEurope.5,6_In Portu-gal,sporadiccaseshavebeenreported,andastudyon237 individuals,fromwhich152werepatientsfroma Gastroen-terologyDepartment,showed that4.2% of thepopulation enrolledwasseropositiveforanti-HEV.Furthermore,inthe seropositive group, only 20% hada history of traveling to endemiccountries.7

Testing for hepatitis E should be done in the diagnos-ticanalysis ofall patients withacuteor chronic hepatitis thatcannotbeexplainedbyothercauses.AcuteHEV infec-tionisdiagnosedinimmunocompetentindividualsbasedon the detection of anti-HEV IgM. Immunocompromised indi-viduals should always be tested for HEV RNA, if there is suspicionthattheyareinfected,becauseseroconversioncan bedelayedinthesepatients.8,9

Mostinfectionshavea clinicallysilent course.In symp-tomatic cases, the incubation period ranges from 2 to 8 weeks, with a mean of 40 days.1 _{Initial symptoms of} acutehepatitisEaretypicallyunspecificandincludeflu-like myalgia,arthralgia,weaknessandvomiting.However,more

severeforms ofacute liverdiseasecan occur inpregnant womenor patients withunderlying chronicliver diseases, sometimes progressing to fulminant hepatic failure.10 _In immunocompetentpatients,HEVismainlyself-limitedand causes no chronic evolution. In fact, in these individ-uals,acutehepatitisE does notusuallyrequiretherapy.11 Nevertheless, in immunocompromised patients, HEV can pursueachroniccourse.PersistentHEVinfectionwasfirst reportedin2008in8Frenchsolidorgantransplantrecipients onimmunosuppression.Furthermore,onekidney-transplant patienthadcirrhosis attributedtochronic HEVinfection.2 HEV-associatedliver cirrhosis or hepatocellular carcinoma intheimmunocompetentpatienthasnotbeenreported,so far;however,acuteHEVinfectionisknowntobeacauseof decompensatedlivercirrhosis.12

Case

report

A24-year-old puerperal woman was admittedto our Ter-tiaryCare MedicalCenterwith acutehepatic failure.She wasa Pakistaniwoman living in Portugalfor 3 yearsthat hadrecentlytraveledtoPakistanwhilepregnant,foratotal stayof3months.ShereturnedtoPortugalduringthethird trimesterofherpregnancy,3weeksbeforeadmissioninour Hospital.DuringhertimeinPakistan,shewasobservedby anObstetriciananddidafetalultrasoundthatshereported asbeingnormal.Shedeniedhavinganysymptomswhilein Pakistan,contactwithsickpeopleand/or previoushistory ofhepatitisinherrelatives.Herbackgroundwas unremark-able,she wasmarried andmotherofa2-year-oldhealthy child,witharegularpregnancyandaneutocicdeliveryand ahistoryof 2previous spontaneousabortions. Shedenied currentmedicationandtoxicoralcoholconsumption.

Duringpregnancyweek32,thepatientreportednausea, vomiting, asthenia and myalgia. She went to an outpa-tient Obstetrics Consult in another Institution and in the

same day wasreferred to the emergency room, because she alsohad jaundice. She did not recall whathappened next.Atthatpoint,bloodtestsshowedhighliverenzymes (transaminases aspartate transaminase [ALT] and alanine transaminase [ALT]) and hyperbilirubinemia. Labor was inducedandshedeliveredahealthyfemalebaby.Duringthe next12h,shedevelopedgradeIencephalopathy,therefore beingtransferredtothe ICU of ourhospital.Upon admis-sion, examination showed that she was markedlyicteric, withgradeIIIencephalopathy(GlasgowComaScale:6).She washypothermic(34.7◦C),hemodynamicallystable, with-out palpable hepatomegaly, and her uterus was palpable 3cm above her pubic symphysis. Laboratory values upon admission showed significant elevations in AST (406IU/L [normal,10---37UI/L]),ALT(569IU/L[normal,10---37UI/L]), lactatedehydrogenase(1358[normal,205---423UI/L]), alka-linephosphatase354UI/L[normal,44---155UI/L]andNH347 ([normal,8---33␮mol/L]).Bilirubinwassignificantlyelevated (41.20mg/dL,[normal,0.4---1.2mg/dL]),withunconjugated bilirubin of 10.6mg/dL. Gamma-glutamyl transpeptidase (GGT)wasslightlyelevated(63UI/L[normal,10---49UI/L]). Arterial lactic acid was elevated (34mg/dL [normal, 4.5---14.4mg/dL]).Prothrombintimewasprolonged(PT-INR, 5.4[normal,0.81---1.38]),and factorVactivity was dimin-ished(15.1%). Shehada normalplateletcount.The head CTscanwasnormalandtheabdominalultrasoundshowed normal liver echogenicity without structural abnormali-ties,withpatent,non-occludedlivervasculature.Screening for hepatitis A, B, C and G, syphilis, cytomegalovirus, herpes simplex virus, toxoplasmosis, leptospirosis, antin-uclearantibodies (ANA), smooth muscle antibodies (SMA) and antibodies to liver/kidney microsome type 1 (LKM1) werenegative.PCR for Hepatitis E RNA wasstrongly pos-itive, so she was diagnosed with acute hepatic failure causedbyacutehepatitisE,withhepaticencephalopathy. She was listed for urgent orthotopic liver transplanta-tion (OLT) and immediately started on extracorporeal albumin dialysis (Prometheus®_{), but clinical deterioration} occurred within 48h Given her low Glasgow Coma Scale of 3, mechanical ventilation was required. She under-went OLT at day 4 post-admission. Her explant had no major macroscopic alterations, except a slight softening ofitsconsistency.Thehistologicalanalysisrevealed exten-sive areas of confluent panlobular, non-zonal necrosis, withporto-portal,porto-centralandcentro-centralbridges. The residual parenchyma showed ballooned hepatocytes, marked pseudo-rosettes formation and cholestasis, either cytoplasmaticor inthecenteroftherosettes(cholestatic rosettes). Lobular inflammation with lymphocytes, plas-mocytes,some neutrophilsandnumerous histiocyteswere alsodetected (Figs. 1---3). Immediate graft function post-transplantwasgoodandshehadanunremarkablerecovery. SerumHepatitis ERNA (PCR)wasnegative2monthsafter transplantation.

Genotypeanalysis,performed incollaborationbetween MolecularDiagnosticSection,ClinicalMicrobiology&Public HealthLaboratoryAddenbrooke’sHospital(Cambridge),UK ReferenceLaboratory andMicrobiologyDepartment, Medi-calSciencesUniversity(Lisbon)confirmedthatthevirusis HEV.However,maximalsimilaritywithmorethanone geno-typewasobserved,meaningthatthisHEVcouldbeanew genotype.

Figure1 Extensiveareas ofconfluentnecrosisand pseudo-rosettesformation(H&E50×).

Figure2 Markedhepaticnecrosiswithregenerative pseudo-rosette formation. There is cholestasis and moderate mixed inflammatoryinfiltrate(H&E400_×).

Figure3 Hepatocyteballooning(H&E400_×).

The newborn was icteric at birth, with total bilirubin of 14.8mg/dL andpositive IgGanti-HEV and negativeIgM anti-HVE.Sheunderwentphototherapytreatment,plusone exchangetransfusion,withnormalizationoftotalbilirubin.

After3weeksattheneonatalICU,shewastransferredto thePediatricDepartment,where shewasreleased after7 weeks.

Discussion

In a general population living in a country where HEV is endemic, mortality associated with fulminant hepatitis is approximately1%.5_{ThesesevereformsofHEVaremore} pro-nouncedinpregnantwomen,in whichmortalitycanbeas highas20---30%.13

There is a complex interaction among viral, host, immunologicalandhormonalfactors,producingaparadigm ofsevereliverdamageinpregnancy.Thematernalimmune systemisclearlyalteredtotolerateageneticallydifferent fetus.14 _{Theseimmunologicalchangespromotethe} mainte-nanceoftheantigenicfetusinthematernalenvironmentby suppressionof T-cell-mediated immunity. There is aclear shiftin theT-helper type1 (Th1):Th2 cellparadigm dur-ingpregnancy,withadefinite skewtowardTh2 cells.The levelsofmostcytokinesaredepressed,particularlyduring theinitial20weeksofpregnancy.CD4countsaregenerally lowerinHEVpositivepregnantpatients,whileCD8counts are higher. The ratio of CD4/CD8 in these patients with fulminanthepaticfailurewassignificantlylowerwhen com-paredtoHEVnegativepatientsorcontrols.15_Viralloadand genotypeshavebeenimplicatedintheseverityofliver dis-ease,andHEVviralloadwasfoundtobesignificantlyhigher in pregnantwhencomparedtothe non-pregnant.16 Geno-type 1 and 4 are the most common subtype causing HEV infectioninendemiccountriesasPakistan,whilegenotype 3predominates inthe US.The genotype ofthispatientis not available yet, and even though thereis some specu-lationregarding the influence of the genotype onclinical featuresin thissetting, thatremains tobeproven.16 Fur-thermore,thereareevidencesindicatingthathighersteroid hormonelevels,aspresented duringpregnancy,may influ-enceviralreplication.17_{Forthetimebeing,althoughthere} isnoconsensusonhowtotreatpatientswithHEVinfection inpregnancy,earlydeliveryofthefetus,ifpossible,should beattempted,topreventmaternalmortality.17

Mostofthedescribedcasesofacutehepaticfailure asso-ciated to HEV during pregnancy had a favorable clinical course,butpatientsdevelopingfulminantliverfailurehad ahigher mortalityrate.13,18---20 _{However,astudy byBhatia} et al. showedthat oncefulminant hepatitis appears, the mortalityratemightbesimilarinpregnantwomenwith hep-atitisEandinthosewithothercausesofsevereliverinjury.10 However,despitethisfinding,thehigherincidenceof symp-tomatic disease and that of FHF amongpregnant women exposedtoand/orinfectedwithHEVimpliesthattheoverall mortalityrateamongpregnantwomenismuchhigherthan non-pregnantwomanandmenduringoutbreaksofhepatitis E.21

Livertransplantisconsideredanoption,butitisunknown whether its outcomes in this setting are different from othercausesofacuteliverfailure.Furthermore,vertically transmittedHEVinfection throughcordbloodis knownto causeacutehepatitisinnewbornbabies.Khurooetal. stud-ied19 newbornbabies born toHEVinfected mothers and showedthat 78.9% n=15of thosebabieshad evidenceof

verticallytransmittedHEVinfectionatbirth.Sevenbabies died in the first week after birth and all the surviving babieshadself-limiteddisease,while nonehadprolonged viremia.22

Asthemajorityofcasesareself-limited,liverbiopsyis notusuallyperformed,sothehistologydataaboutHEVacute hepatitisarescarce.However,severalcasesofacuteHEVin thewesternworldhaverecentlybeendiagnosedwith histo-logicalanalysis.23,25,26_{Malcolmetal.assessedliverhistology} from patients with acute HEV, either locally acquired or importedfromendemicareas,andfoundsomedifferences. Thelatterleadstospottyorconfluentnecrosis,portaland lobular inflammation, ballooning degeneration of hepato-cytes,intracytoplasmicandintracanalicularcholestasisand hepatocytepseudo-rosette formation, in accordance with thefeaturesofourcase.24_{Ontheotherhand,sporadiccases} showgeographicalvariationoftheportalinflammatory infil-trate,withpolymorphsattheperipheryandinterface,while lymphocytes at the center, perivenular edema with hep-atocyte loss, aggregates of lipofuscin-containing Kupffer cells,necrosisandfibrosisofzone3andnopseudo-rosette formation.23 _{However, these differences are not clearly} defined and both forms may have cholestatic features.25 TheseaspectsareclearlydifferentfromchronicHEV infec-tioninimmunocompromised individuals,astheypresenta denselymphocyticportalinfiltrate,piecemealnecrosisand fibrosis,similartocasesofHCV.26

Agrawaletal.comparedthehistologyoffulminantHEV with fulminant HBV cases and found that interface hep-atitiswassignificantlymorefrequentinpatientswithHBV thaninthosewithHEV.Althoughnotreachingstatistical sig-nificance, ballooning, pseudo-rosette formation, steatosis andplasmacellsweremoreprevalentinHEV.The pseudo-rosettes(astrikingfeatureofourcase)areuncommoninthe westerncasesandfrequentinthecasesinendemicareas.25 Thehistologicalaspectsofourcasearesimilartothose foundbyMalcolmetal.andAgrawaletal.inendemicareas, whichcorrelateswiththeanamnesis.Althoughthecorrect diagnosis is aserologic one,it seemsthere aresome his-tologicalaspectsthatcangiveaclueontheHEVetiology, andevensomedifferencesintheendemic/sporadiccases, probablyreflectingdifferentgenotypes.24

Asfarasweknow,thisisthefirstcasereportinPortugal fromapregnantwomanwhodevelopedhepaticfailuredue tofulminant hepatitis Ethat underwentasuccessfulliver transplantation.

Ethical

disclosures

Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.

Confidentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdataandthatallthepatientsincludedinthe studyreceivedsufficientinformationandgavetheirwritten informedconsenttoparticipateinthestudy.

Right to privacy and informed consent.The authors declarethatnopatientdataappearinthisarticle.

Conflicts

of

interest

Theauthorshavenoconflictsofinteresttodeclare.

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