www.analesdepediatria.org
ORIGINAL
ARTICLE
Acute
liver
failure
related
to
inherited
metabolic
diseases
in
young
children
夽
Filipa
Dias
Costa
a,∗,
Filipa
Dias
Costa
a,∗,
Rita
Moinho
a,
Sandra
Ferreira
b,
Paula
Garcia
c,
Luísa
Diogo
c,d,
Isabel
Gonc
¸alves
b,
Carla
Pinto
a,daServic¸odeCuidadosIntensivosPediátricos,HospitalPediátrico,CentroHospitalareUniversitáriodeCoimbra,Portugal bUnidadedeTransplantac¸ãoHepáticaPediátricaedeAdultos,HospitalPediátrico,CentroHospitalareUniversitáriodeCoimbra,
Portugal
cUnidadedeDoenc¸asMetabólicas-CentrodeDesenvolvimentodaCrianc¸a,HospitalPediátrico,CentroHospitalareUniversitário
deCoimbra,Portugal
dFaculdadedeMedicina,UniversidadedeCoimbra,Portugal
Received17December2016;accepted15February2017
KEYWORDS
Pediatric;
Acuteliverfailure; Inheritedmetabolic diseases
Abstract
Introduction:Pediatricacuteliverfailure(ALF)duetoinheritedmetabolicdiseases(IMD)isa rarelife-threateningconditionwithapoorprognosis.Earlyinterventionmaybelifesaving. Objective: Todescribeclinicalpresentation,investigationandoutcomesofALFrelatedtoIMD inyoungchildren.
Materialandmethods: Retrospectivereviewofthemedicalrecordsofchildrenagedupto24 months, admittedtoatertiary pediatric andneonatalIntensive CareUnitduring a27-year period,fulfillingtheALFcriteria,withdocumentedmetabolicetiology.
Results:From 34 ALFcases, 18 were related to IMD: galactosemia (4), mitochondrial DNA depletion syndrome(MDS)(3),ornithinetranscarbamilase deficiency(3),congenitaldefects of glycosylation (2), tyrosinemia type 1 (2), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (1), hereditary fructose intolerance (1), classic methylmalonic aciduria (1) and citrulinemia type 1 (1).The median agewas 1.3 months. Atleast oneprevious suggestive sign/symptom of IMD (vomiting, failureto thrive, hypotonia or developmental delay) was observedin67%ofthecases.Themostcommonphysicalsignsatadmissionincluded: hepato-megaly(72%),jaundice(67%)andencephalopathy(44%).Thepeaklaboratorialfindingswere: meaninternationalnormalizadratio4.5,medianlactate5mmol/L,meanbilirubin201mol/L, medianalanineaminotransferase(ALT)137UI/Landmedianammonia177mol/L.Onepatient wassubmittedtolivertransplantinALFcontext(MSD).Themortalityratewas44%.
夽 Pleasecitethisarticleas:DiasCostaF,MoinhoR,FerreiraS,GarciaP,DiogoL,Gonc¸alvesI,etal.Insuficienciahepáticaagudaasociada
aenfermedadesmetabólicashereditariasenni˜nospeque˜nos.AnPediatr(Barc).2017.http://dx.doi.org/10.1016/j.anpedi.2017.02.012 ∗Correspondingauthor.
E-mailaddress:filipacdcosta@gmail.com(F.DiasCosta).
2341-2879/©2017PublishedbyElsevierEspa˜na,S.L.U.onbehalfofAsociaci´onEspa˜noladePediatr´ıa.
Discussion: TheidentificationofIMDasafrequentcauseofALFallowedspecifictherapeutic measuresandadequatefamilycounseling.ParticularclinicalfeaturesandmoderatedALTand bilirubinlevelscanleadtoitssuspicion.
©2017PublishedbyElsevierEspa˜na,S.L.U.onbehalfofAsociaci´onEspa˜noladePediatr´ıa.
PALABRASCLAVE Pediátrico; Insuficienciahepática aguda; Enfermedades metabólicas hereditarias
Insuficienciahepáticaagudaasociadaaenfermedadesmetabólicashereditariasen ni˜nospeque˜nos
Resumen
Introducción:La insuficiencia hepática aguda(IHA)secundaria aenfermedadesmetabólicas hereditarias(EMH) esunaenfermedadgraveinfrecuentedemalpronóstico.Laintervención tempranapuedesalvarvidas.
Objetivo:Describir lapresentaciónclínica,lainvestigaciónylaevolución deIHA asociadaa EMHenni˜nospeque˜nos.
Materialymétodos: Estudioretrospectivodelashistoriasclínicasdeni˜nosconedaddehasta 24mesesingresadosenunaunidadterciariadecuidadosintensivosneonatalesypediátricos, duranteunperíodode27a˜nos,quecumplíanloscriteriosdiagnósticosdeIHAyconetiología metabólicadocumentada.
Resultados: Delos34 casos deALF, 18 seasociaban aEMH:galactosemia (4),síndrome de deplecióndelADNmitocondrial(SDM)(3),deficienciadeornitinatranscarbamilasa(3), defec-toscongénitosdelaglucosilación(2),tirosinemiatipo1(2),deficienciade3-hidroxi-acil-CoA deshidrogenasadecadenalarga(1),intoleranciahereditariaalafructosa(1),aciduria metil-malónicaclásica(1)ycitrulinemiatipo1(1).Laedadmedianafuede1,3meses.Enel67%de loscasossehabíaobservadoalmenosunsíntomaosignoindicativodeEMHconanterioridad (vómitos,fallodemedro,hipotoníaoretrasodeldesarrollo).Lossignosfísicosmásfrecuentes enelmomentodelingresofueron:hepatomegalia(72%),ictericia(67%)yencefalopatía(44%). Losnivelesanalíticospicofueron:razóninternacionalnormalizadamedia,4,5;lactato medi-ano,5mmol/L;bilirrubinamedia, 201mol/L;alaninaaminotransferasa (ALT)mediana,137 UI/L;yamoniomediano,177mol/L.Unpacientefueremitidoparatrasplantedehígadoen contextodeIHA(MSD).Latasademortalidadfuedel44%.
Discusión: LaidentificacióndeEMHcomocausafrecuentedeIHApermitióelusodemedidas terapéuticasespecíficas yunasesoramientofamiliarapropiado. Susmanifestacionesclínicas particularesynivelesmoderadosdeALTybilirrubinapuedenllevarasospecharestacondición. ©2017PublicadoporElsevierEspa˜na,S.L.U.ennombredeAsociaci´onEspa˜noladePediatr´ıa.
Introduction
Pediatricacuteliverfailure(ALF)isararelife-threatening conditionthatmayprogressquickly,withsevereimpairment of hepaticfunction. It can berecognizedby hepatocellu-lar necrosis and refractory coagulopathy with or without encephalopathy. The etiology of ALF varies according to theage of the patientand geographicareas. In neonates and infants, viral infections (enteroviruses, herpes sim-plex and others), neonatal hemochromatosis, inherited metabolic diseases (IMD) and hemophagocytic lymphohis-tiocytosis are the main causes. In older children, the most common causes are drug-induced ALF, autoimmune hepatitis and viral infections, being hepatitis A virus the most frequent in developing countries.1 Inherited
metabolic diseases deserve special attention in differ-ential diagnosis of pediatric ALF, particularly in infants and young children, in whom they constitute 13---43% of all cases.2 In the first 3 years of life, the commonest
IMD related to ALF are: galactosemia; tyrosinemia type 1; mitochondrial cytopathy; fatty acid oxidation defect;
hereditary fructose intolerance; urea cycle defect and congenital disorders of glycosylation.2 In this particular
age group, it is fundamental to conduct an exhaustive, structuredandexpeditiousdiagnosticwork-uptominimize indeterminatecasesthatcouldbeexplainedbyan unrecog-nizedIMD.
Theprognosis ofIMDrelatedALF isgenerallypoor and depends on the specific diagnosis.3 Early recognition of
these etiologies is essential, since some require disease-specifictreatment ormayconstituteacontraindicationto liver transplantation (LT), as in cases with multisystemic involvement.1,2,4LTcanimprovetheoutcomeinIMDcases
whofailtorespondtoconservativemanagement.2,5
To improve IMD diagnosis and intervention in ALF cases, a better knowledge of their clinical presenta-tion and biochemical markers is fundamental. The aim of this study was to characterize the clinical presenta-tion, laboratory profile and outcome of young children admitted to a pediatric and neonatal intensive care unit (ICU) with ALF related to IMD, during a 27-year period.
Methods
This is adescriptivestudy conductedin thepediatric and neonatalICUofatertiaryuniversityhospital,thenational referral centerfor pediatriclivertransplantation. Medical recordsofallchildrenagedupto24monthsadmittedtoICU duringa27-yearperiod,(betweenJanuary1989and Decem-ber2015),fulfillingALFcriteriaandwithadocumentedIMD werereviewed.
Acute liver failure was defined according to Pediatric AcuteLiverFailureStudyGroup6bythefollowingcriteria:
(1) children withno known evidence of chronic liver dis-ease; (2) biochemical evidence of acute liver injury, and (3)presence ofhepatic-based coagulopathy,with interna-tionalnormalizedratio(INR)≥1.5notcorrectedbyvitamin Kinthepresenceofhepaticencephalopathy(HE)orINR≥2 regardlessofthepresenceofHE.Encephalopathywas eval-uated by electroencephalogram and/or by clinical signs, classified in four grades: grade 1 --- changes in behav-ior, minimal change in level of consciousness and altered sleep;grade2---drowsiness,confusion,inappropriate behav-ior, disorientation,moodswings;grade3--- somnolentbut arousable,grossdisorientation,bizarrebehavior,muscular rigidity, clonusandhyperreflexiaandgrade4 ---coma and decerebration.1,7
Demographic data,family background, medical history andclinicalsignsandsymptomsatadmissionwereanalyzed. Peak levels of white blood cell (WBC) count, INR, lac-tate,ammonia,totalbilirubinandalanineaminotransferase (ALT),aswellasinitialglycemiaandminimumlevelsof albu-min wererecorded.Baselinemetabolic work-upincluded: acyl-carnitine profile, plasma and urinary amino acids and urinary organic acids profiles, plasma carbohydrate-deficient transferrin, urinary reducing substances and ketones.Otherlaboratoryandmetabolicinvestigationswere carried out in a case by case approach. DNA extraction wasperformedforspecificmolecular/geneticstudies.Other informationcollected included results of molecular tests, timingof theconfirmationof etiologicaldiagnosis (invivo
orpost-mortem),decisiononlivertransplantation,timeto ICUdischarge,mortalitytodischargeandoverallmortality. Statistical Package for the Social Science® version 20
wasusedforstatisticalanalysis.Quantitativevariableswere evaluatedbymeasuresofcentraltendencyandofdispersion andqualitativevariablesbydeterminationoffrequencies.
Results
Duringthe study period,fromatotal of 34children aged up to 24 months admitted at ICU with ALF, in 18 cases an IMD was confirmed. The median age was 1.3 months (Q1:0.2; Q3:5.5), 8/18 were newborns and 8/18 were boys.
TheetiologicalIMDsidentifiedandtheresultsofgenetic investigationaredepictedinTable1.Inthecaseof hered-itaryfructoseintolerance,thediagnosiswasestablishedby enzymatic study in a liver biopsy, which showed reduced capacity of aldolase to split fructose-1-P and a ratio of fructose-1,6-bisphosphate/fructose-1-P of 38 (N≈1). The youngest patients were diagnosed during the neonatal periodwithgalactosemia(3),mitochondrialDNAdepletion
Table1 ALFetiologiesandgeneticinvestigations.
IMD n Geneticinvestigation
Galactosemia 4 GALTgene:Q188R (homozygous)(2) GALEgene: p.Val94Melc.280G>A (homozygous)(2) MDS 3 DGUOKgene: c.677A>G (homozygous)(2)and c.749T>C (homozygous)(1) OTCdeficiency 3 OTCgene:Tyr143
stopexon5(1);R92Q CGA>CAAcodon92 (1)andR23X CGA>TGAcodon23, exon1(homozygous) (1)
CDG 2 CCDC115gene:
p.leuc31Serc.92T>C (1)
Tyrosinemiatype1 2 FAHgene: IVS6-1(G>T)/IVS7+1(G>A) (1)andIVS6-1(G>T) (homozygous)(1) LCHADdeficiency 1 HADHAgene:G1528C
(homozygous) Hered.fructoseintolerance 1
---cMMA 1 MUTgene:
c.1172delA (p.D391Vfs*9) (homozygous) Citrulinemiatype1 1 ASS1gene:c.970G>A
(p.G324S) (homozygous)
ALF:acuteliverfailure;CDG:congenitaldisorderof glycosyl-ation; IMD: inherited metabolic diseases; LCHAD: long-chain 3-hydroxyacyl-CoA dehydrogenase; MDS: mitochondrial DNA depletion syndrome; cMMA: classic methylmalonic aciduria; OTC:ornithinetranscarbamylase.
syndrome(MDS)(2),ornithinetranscarbamilase(OTC) defi-ciency (1),classic methylmalonicaciduria (cMMA)(1)and citrulinemiatype1(1).
Informationaboutconsanguinitywasavailablein13/18, beingpositivein3.Familyhistorywasunremarkableinall buttwocases: oneof a patientwithMDS, whose brother died in another hospital with the diagnosis of neonatal hemochromatosis, later proved to also be a MDS due to deoxyguanosinekinase(DGUOK)deficiency;andacaseofa newborn,sisterofanelderpatientalreadyincludedinthis study,whodiedwithALFandwhosepost-mortem investiga-tionallowedtomakethediagnosisofgalactosemiadueto galactoseepimerase(GALE)deficiencyinbothsiblings.
Retrospectively, 67% (12/18) of the cases had at least oneof thefollowing signs/symptoms: vomiting;failure to thrive;hypotoniaanddevelopmentaldelay.Themost com-mon physical signs at admission included: hepatomegaly (13/18;72%);jaundice(12/18;67%);encephalopathy(8/18;
Table2 PresentingphysicalsignsofALFaccordingtoetiology.
IMD n Jaundice Hepatomegaly Splenomegaly Encephalopathy Ascites
Galactosemia 4 4 4 0 2 0 MDS 3 3 3 0 0 2 OTCdeficiency 3 1 1 0 2 0 CDG 2 1 2 2 1 2 Tyrosinemiatype1 2 1 0 0 0 2 LCHADdeficiency 1 0 1 1 1 0
Hered.fructoseintolerance 1 0 1 0 0 1
cMMA 1 1 1 0 1 0
Citrulinemiatype1 1 1 0 0 1 0
ALF: acute liver failure; CDG: congenital disorder of glycosylation; IMD: inherited metabolic diseases; LCHAD: long-chain 3-hydroxyacyl-CoAdehydrogenase;MDS:mitochondrial DNAdepletionsyndrome;MMA:classicmethylmalonicaciduria;OTC:ornithine transcarbamylase.
Table3 Laboratorialparametersaccordingtoetiology. Parameter
Initialglycemia mean(±SD) 5.5(±3.2)mmol/L Peakammonia median(Q1---Q3) 177(68---281)mol/L Peaklactate median(Q1---Q3) 5(3.5---6.8)mmol/L PeakINR mean(±SD) 4.5(±2.6)
Minimumalbumin median(Q1---Q3) 23(17---26)g/L PeakWBC mean(±SD) 18.6(±9.0)×109/L PeakALT median(Q1---Q3) 137(73---500)UI/L PeakBRBt mean(±SD) 201(±170)mol/L
ALT:alaninaaminotransferase;BRBt:totalbilirubin;INR: inter-nationalnormalizedratio;SD:standarddeviation;WBC:white bloodcells.
44%);ascites(7/18;39%)andsplenomegaly(3/18;17%).5/8 patientshadsevereencephalopathy(grades3---4).The phys-icalsignsatadmission,accordingtotheunderlyingIMD,are describedinTable2.
Data concerning mean or median peak levels of WBC count, INR, lactate, ammonia, total bilirubin, ALT, initial glycemia and minimum levels of albumin are shown in
Table3.Etiologicaldiagnosiswasconfirmedbyfurther
inves-tigations requested ona child-to-child basis, except in 5 casesinwhichthediagnosticsweredoneinthepost-mortem
period[2MDS,1 longchain Long-chain 3-hydroxyacyl-CoA dehydrogenasedeficiency(LCHAD),1 congenitaldefectof glycosylation(CDG) and1 galactosemiadue toGALE defi-ciency].
The retrospective analysis of physical and laboratorial featuresallowedtheidentificationofsomeparticular char-acteristicsinpatientswiththesameIMD.Bothpatientswith tyrosinemiatype1presentedrenaltubulopathy.The4cases of urea cycle disorders (OTC deficiency and citrulinemia type1) presentedhighlevelsofammoniawhen compared withotheretiologies:median333mol/L(Q1:118;Q3:1703)
vs 172.5mol/L (Q1:61.8; Q3:236.5), respectively. In the galactosemiadue toGALE deficiency, hypotonia, bilateral hipdysplasia and short staturewere features common to both cases. Short stature, some facial dysmorfisms and hepato-splenomegaly were present in both cases of CDG. The3patientswithMDSduetoDGUOKdeficiencyrevealed
a positive historyof consanguinity, hypotonia, nystagmus, hypoglycemia andhigh levels of ferritin[789;1931]ng/mL (normal range:9---120) and tyrosine [68;543]mol/L (nor-malrange:28---96).ThepatientwithLCHADpresentedwith cardiogenicshock.
Liver transplant was performed in ALF context in one patientwithMDS.Itwasdecidedbyamultidisciplinaryteam attheageof4monthsduetorecurrentliverfailure,before the molecular confirmation of DGUOK deficiency, despite neurologicdysfunctionandrotatorynystagmus.However,he diedat4yearsofageduetoanintercurrencewithmetabolic acidosis, hyperlactacidemia and cardiorespiratory arrest. AnotherpatientwithtyrosinemiawassubmittedtoLTlater on,attheageof7years,duetounsatisfactorymetabolic control, osteopenia, renal tubulopathy and hepatic nodules.
Analyzing the outcomes, the median time to ICU dis-charge was 7 days (Q1:3; Q3:21). The mortality until discharge and overall mortalitywere 39% (7/18) and 44% (8/18), respectively. Besides the MDS patient mentioned above, the diagnosis of the other 7 deceased patients were: MDS (2), LCHAD (1), CDG (1), galactosemia due to GALEdeficiency(1),OTCdeficiency(1)andcMMA(1).The major causes of death were due to progression to mul-tiorgan failure or cardiogenic shock. In 3 of these cases (CDG, OTCdeficiencyandcMMA),theadjustmentof ther-apeutic effortwasdecidedinmultidisciplinary consensus, based on the conditions described hereafter: (1) In the CDGcase, despiteoptimizedtherapeuticmeasures includ-ingconsiderationforLT,themultisystemicinvolvementwith unfavorable neurological evolution due tosevere hypoxic ischemiclesionsdocumentedbyimagingstudiesprecluded this option; (2) In thecase withOTC deficiency, the high ammonia (>800mol/L) levels were difficult to control during the first 48hours, despite maximum therapeutic measures, including hemodiafiltration. Although ammonia levelsdecreasedafterwards,noneurologicalimprovement wasachieved.Thepatientprogressedtomultiorganfailure, exacerbatedbyaKlebsiellaoxytocasepsis;(3)InthecMMA case,despitepromptprovidingofspecifictherapeuticsand reductionofammonialevels,theclinicalevolutionwas unfa-vorablesinceadmissionwithrapidprogressiontomultiorgan failure.
Discussion
Thedisordersthatcanleadtoliverfailureinthepediatric agegroupupto24monthsarequitespecificandIMDs rep-resentoneofthemostfrequentetiologies,withadescribed frequency of 13---43%.2 In the present study, from a total
of 34 children with ALF in this age group, 18 (53%) were diagnosedwithanIMD.ThishighnumberofidentifiedIMDs resultsfromaprogressiveefforttocarryoutamore compre-hensivediagnostic investigation,evenin thepost-mortem
period.Itcanalsobeexplainedbytherecognitionof this tertiaryhospitalastheuniquereferralcenterinPortugalfor LTandALFsince1994and2008,respectively.Patients with-outareadilyidentifiablecauseofALFmustbeconsideredfor furtherscreeningformetaboliccausesofALF,especiallyin thisagegroup.PediatricALFetiologyremainsindeterminate in18---47%,1dependingupontheexhaustivenessofwork-up
screening, andit caneven behigherin youngerchildren, approaching54% inchildrenunder3years,asreportedby Squiresetal.6
EarlyrecognitionofIMDsiscrucial,becausesomerequire immediateinitiation of specific therapy or diets that can belife-saving,mainlyinthecaseofgalactosemia, heredi-tary fructoseintolerance andhereditary tyrosinemia type 1,1 which can present during neonatal period with
jaun-dice, hypoglycemiaand sometimes withALF.8 In thiscase
series,thelowernumberofpatientswithgalactosemiaand hereditary tyrosinemia type 1 presenting with ALF, com-pared to King’s College experience,9 may be attributed
totheexpanded Portuguese neonatalscreening,available since2005,whichallowspre-symptomaticdiagnosisofthese diseases.
The scarce consanguinityinformationavailable(inonly 13/18)isalimitationrelatedtotheretrospectivenatureof thisstudy.AccordingtoHegartyetal.,9historyofparental
consanguinity can be present in 44% of IMD related ALF. Particularitiesofthefamilialhistory,suchasrecurrent abor-tions,sibling deathsandpreviously affectedchildren, are otherfeaturesthatmustalwaysbeexplored,sincetheycan raisethesuspicionofIMDs,asfoundinthecasesofMDSand galactosemiaduetoGALEdeficiency.
Theprevioushistoryofvomiting,failuretothriveand/or developmental delay, present in 67% of cases, is another strong pointer suggesting an IMD, as suggested by Alam et al.,2 and Brett et al.4 Encephalopathy was more
fre-quent(44%)whencomparedtoHegarty’sIMDseries9(19%),
afactthatcanbeexplainedbythedifferentratioofeach specificIMDinbothsamples.Otherreasonthatcould con-tribute to this result was the possible delay in referral to our center occurred prior to 2008, date of its incep-tion as national referral center for ALF.10 Some clinical
featurescanprovidecluestoaspecificIMD,guidingthe eti-ologicalinvestigation.11 The cardiacinvolvementcan lead
toLCHAD suspicion.Some dysmorphismsareknown tobe more frequent in CDG and in galactosemia due to GALE deficiency.11,12Thetriadofhypotonia,nystagmusand
hypo-glycemiaistypicallypresentinMDSduetoDGUOKdeficiency cases.These patients canalsohave high levelsof ferritin andtyrosine,leadingtothedifferentialdiagnosisof neona-talhaemochromatosisandtyrosinemiatype1.13Otherclues
fromlaboratorialresultsaresignsoftubulopathy,thatmay
suggesttyrosinemiatype1,classicgalactosemiaor hered-itary fructose intolerance and marked hyperammonemia whichisatypicalfindinginureacycledisorders.11
Regardingthelaboratorialparameters,theslightto mod-erateelevationofALTobservedisconsistenttolevelsfound inotherstudiesof IMDrelatedALF9,14 andinferiorthanin
otheretiologies,especiallyinviralinfection.14 The
moder-ateelevationofbilirubinlevelswasalsosimilartofindingsof otherstudies.9,14 Intwosmallseries4,15thatcompared
lab-oratoryprofile inIMDrelatedALFwithothercauses, peak levelsof lactateandammoniaweresimilarbetween both groupsandalsoidenticaltolevelsfoundinthisstudy, sug-gestingthattheymaynotbeusefulasisolatedmarkersof IMDinALF.
The recognition ofIMD iscrucial tooptimizethe man-agementwithtargetedintervention,toevaluatetheneed for LT and to do adequate parental counseling in future pregnancies.16 Decisions on transplantation areextremely
difficult, a fact that is corroborated by the lack of vali-datedpediatricALFprognosticmodels,17especiallyforIMD
etiology.LT maybecontraindicated incasesin whichALF mayresolve with specific medicaland/or diet therapy,if theunderlying diseaseinvolvesotherorgansor systemsor ifthereisa rapidprogressionof ALFwithmultiorgan fail-ureor sepsis.5,18 Of the18 patientsincluded in thisstudy
only1wassubmittedtoLTin ALFcontext,apatientwith DGUOKdeficiencythatreceivedaLT,despitethepresence ofneurologicdysfunctionandrotatorynystagmus.However, itdidnotpreventdiseaseprogression,withneurologicand visualimpairment,severepsychomotordelayandfailureto thrive.Inthishepato-cerebralmitochondrialDNAdepletion syndrome,thecontra-indicationforLTisunclear,sincethere arealsosomedescriptionsintheliteratureofasignificant proportionofpatientswhobenefitfromLTwithgood long-term survival and a stable neurological situation despite initialneurologicalabnormalities.19,20
Theoverallmortalityrateof44%waslowerwhen com-paredtothe70%reportedbyAlametal.,15buthigherthan
the19%describedbyHegarty.9Sundarametal.,14 reported
a24%ofmortalitywithoutLT.However,thecomparisonof mortalityratesis hamperedbygroupheterogeneities con-cerning the age, the different etiologies of ALF and the smallcaseseriesnumbers.Infact,whileSundaram14
stud-iedALF in infants upuntil 3 months of age, in Hegarty’s series9childrenwereagedupto5yearsoldandthe
major-ityofdiagnosisweregalactosemiaortyrosinemia,towhich agoodprognosis isgenerallyattributed.In ourstudy,the highpercentageofpatientswithmultisysteminvolvement orwithrapidprogressiontomultiorganfailurecouldexplain themortalityrate.Inaddition,44%patientspresentedwith encephalopathy, which is generally recognized as a poor prognosticmarkerinALF.21
Over the last years, the implementation of expanded newbornscreeningprogramsinseveralcountries,aswellas theavailabilityofnewspecifictherapiesforsomediseases andadvancedsupportivedeviceshavecontributedto mod-ifysomeIMD’snaturalhistoryandprogression.1,4Asshown
in Couceseries22 about the incidence of IMD in a
neona-tal unit, not necessary related to ALF, the investment in an early neonatalscreening can allow the early diagnosis andtreatmentinagroupofpatientsinapre-symptomatic
period,avoidingsevereclinical complicationsandhospital admissioninanumberofcases.
Themainlimitationsofthisstudyarerelatedtothesmall numberof cases,thelarge periodconsidered andthe ret-rospectivedatacollection,thatcouldlimittheinformation obtained.Moreover, onlyALF casesadmitted toICU were includedinthisseries,representingthemostsevereones. Thissampleselectioncouldcreateabias.
ThisstudypointsoutthehighfrequencyofIMDrelated ALFinthisparticular agegroupandthe importanceof an exhaustive diagnostic work-up to reach a correct diagno-sis.The efforttohave apost-mortemdiagnosisallowsfor anadequatefamilycounseling.Someclinicaland laborato-rialfeatures,suchasyoungageandmoderatedelevationof ALTandbilirubinpeaklevels,mayraisethesuspicionofIMD relatedALF.Theearlydiagnosisofthisetiologycanleadto aprompttherapeuticdecision,contributingtoachievinga betteroutcome.Futuredirectionsmuststrivetooptimize therapeuticdecisionsregardingLT,whichmaybeachieved bylargeandhomogeneousmulticentricstudies.
Conflict
of
interest
Theauthorsdeclarethattheyhavenoconflictofinterest.
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