Evaluation of liver function tests in the paediatric patient 夽

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www.analesdepediatria.org

ORIGINAL ARTICLE

Evaluation of liver function tests in the paediatric patient ^夽

Víctor Fernández Ventureira

^a,^∗

, Ignacio Ros Arnal

^a

,

Gerardo Rodríguez Martínez

^b

, Beatriz García Rodríguez

^c

, Ruth García Romero

^a

, Eduardo Ubalde Sainz

^a

aUnidaddeGastroenterologíayNutriciónPediátrica,HospitalUniversitarioMiguelServet,Zaragoza,Spain

bHospitalClínicoUniversitarioLozanoBlesa,UniversidaddeZaragoza,IISAragón,Zaragoza,Spain

cServiciodeBioquímicaClínica,HospitalUniversitarioMiguelServet,Zaragoza,Spain

Received6March2020;accepted4June2020 Availableonline20May2021

KEYWORDS Liver;

Liverfunction;

Asymptomatichyper- transaminasaemia;

Alanine

aminotransferase enzyme

Abstract

Introduction:Althoughchangesinliverfunctiontestscanbenon-specificinnumerousclinical conditions,theycanbethefirstsignofapotentiallyseriousdiseaseinanasymptomaticpatient.

Materialandmethods: Retrospectivecohortstudy,performedbyreviewingtherecordsofchil- drenofareferencehospitalcentrallaboratorywithalanine aminotransferaseenzyme(ALT) elevationduringa6-monthaleatoryperiod.

Results:572bloodtestswithserum ALTelevation correspondingto403patients havebeen assessedduringtheperiodstudied.98patients wereexcludedforpresentingabnormalliver testbeforethestudyperiodofcomorbiditythatcouldproduceALTelevation.Theremaining 305patients,22.6%werediagnosedwithamedicalconditionduringthefirstbloodtestthat explainedtheALTelevation,althoughonly33.3%ofthemwerefollowedupuntilverifyingtheir normalisation.Finalstudy sample consistsof236 patients withabnormal liver test without apparentliverdisease.Adequatefollow-upwasfoundonlyin29%ofthem.Fromthisgroup,9 patients(13%)werediagnosedwithliverdisease.Therestofthesampleswerenotproperly monitored.InpatientswithhigherserumALTlevels,follow-upwasearlyandmoreappropriate.

Conclusions:Inourarea,mostchildrenwithoutapparent liverdiseasearenoproperlymon- itored.Therefore,anopportunitytodiagnosisandtreatapotentialliverdiseasewaslostin agreat number ofchildren. All children with unexplained hypertransaminasaemiamust be studied.

4.0/).

夽 Pleasecitethisarticleas:FernándezVentureiraV,RosArnalI,RodríguezMartínezG,GarcíaRodríguezB,GarcíaRomeroR,UbaldeSainz E.Evaluacióndelseguimientodeni˜nosconhallazgodehipertransaminasemia.AnPediatr(Barc).2021;94:359---365.

∗Correspondingauthor.

E-mailaddress:[email protected](V.FernándezVentureira).

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PALABRASCLAVE Hígado;

Funciónhepática;

Hipertransaminasemia asintomática;

Enzimaalanino aminotransferasa

Evaluacióndelseguimientodeni˜nosconhallazgodehipertransaminasemia

Resumen

Introducción: Lasalteracionesdelperfilhepáticoconstituyenunhechoinespecíficopropiode numerosascondicionesclínicas.Sinembargo,puedeimplicarlaprimeramanifestacióndeuna patologíapotencialmentegraveenunpacienteasintomático.

Materialymétodos:Estudioobservacionalretrospectivoqueincluyetodaslasanalíticassan- guíneasconelevacióndealaninoaminotransferasa(ALT)enpacientespediátricossolicitadas enunsectorsanitarioenunperíodode6meses.

Resultados: Seregistraron572analíticascorrespondientesa403pacientes.Seexcluyeron98 pacientesconhipertransaminasemiayaconocidaocomorbilidad.Delos305restantes,el22,6%

sediagnosticarondepatologíaasociadaahipertransaminasemia,ydeestos,secomprobónor- malizaciónenel33,3%.Delos236pacientesconhipertransaminasemiasinjustificarserealizó unseguimientoenel29%,encontrandopatologíahepáticaen9pacientes(13%delgrupo).En elrestodelamuestranosecomprobóanalíticamentelaevolucióndelastransaminasasnila presenciadeposiblepatologíahepática.Los pacientesconcifras máselevadassecontrolan mejoryantesquelosquepresentancifrasmásbajas.

Conclusiones: Ennuestraárea,lamayoríadelosniñossinenfermedadhepáticaaparentecon hallazgodeALTelevadanosonadecuadamentecontrolados.Estohacequesepierdaunaopor- tunidadúnicadediagnosticarytratarprecozmenteunaenfermedadhepáticapotencialenun grannúmerodeniños.Todoniñoconhipertransaminasemiainexplicadadebeserestudiado.

Introduction

Abnormalitiesintheliverpanelareamongthemostfrequent changes detected inclinical practiceat both the hospital andprimarycarelevels.Routineperformanceofliverpanels hasevincedanincreaseintheincidenceofabnormalserum levelsofliverenzymes,eitherasachancefindinginasymp- tomaticpatientsorinthecontextofmildsymptoms.^1,2

The elevation of liver enzymesis a nonspecific finding presentinmanyclinicalconditions.However,itcanalsobe thefirstmanifestationofpotentiallysevereliverdiseasein anapparentlyhealthypatientorasecondarymanifestation ofaseriousextrahepaticdisease.^1,3,4

Theunderlyingcausesofliverenzymeelevationarehet- erogeneousanddifferbroadlydependingonthepopulation.

Althoughinadultsitismostfrequentlyassociatedwiththe use of alcohol or drugs, inthe paediatric population itis predominantlyassociatedwithtransientinfectiousdiseases (localorsystemic,viralorbacterial).^2,3,5,6

The lack of universal reference valuesin children and theirdependenceonvariousfactors(stageofdevelopment, sex, age, etc.)have prompted theperformance in recent yearsofmultiplestudiesthatattempttoestablishthresh- olds that vary between publications. On the other hand, thereare noestablished clinicalguidelines for the evalu- ationandfollow-upofhypertransaminasaemiainpaediatric practice.^7---18

Nevertheless,itis remarkablethat,despitetheconsid- erablesignificanceofthiscondition,thegeneraltendency at presentis toperforman insufficientfollow-up ofthese patients, globally and in our region in particular. There- fore,theaimofourstudywastoanalysethefollow-upof

patientswithhypertransaminasaemiaandwithoutapparent liverdisease, which hasnot been addressed previously in thepaediatricliterature.

Material and methods

Weconducted a retrospective, observationaland descrip- tivestudy.Weselectedasampleofpatientsaged3months to15years fromthecatchment population corresponding toHealthDistrict II of the city of Zaragoza,Spain, which includes45379childrenaged0---14years.

For the purpose of patient selection, we chose the enzymealanineaminotransferase(ALT,previouslyGPT)due toitshigherspecificityforabnormalliverfunction,including everychildwithserumlevelsexceedingpredefinedthresh- oldsfor sexandage. Weestablishedthe referencevalues basedonthoseproposedbyLamireauetal.¹⁸in2014,which inturntookintoaccountthestudiesconductedbyEngland etal.¹⁰in2009andbySchwimmeretal.¹¹in2010,defining theupperlimitsofnormal(ULNs)for3agegroups:

• 3monthsto18months:60IU/Linboysand55IU/Lingirls.

• 18monthsto12years:40IU/Linboysand35IU/Lingirls.

• 12yearsto15years:26IU/Linboysand22IU/Lingirls.

Weincludedallpatientsinthecatchmentpopulationof theselectedhealthdistrictwithelevationofALTpastthe established thresholds withthe test ordered for any rea- sonat thehospitalor inprimarycare levelsin a6-month period(January1---June30,2016).Weexcludedallpatients withapre-existingdiseaseortreatmentplanthatjustified 360

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serumelevationofALTandpatients withelevationof ALT detected prior tothe period under study. Thus, the final sample includedallpatients inthecatchment areaof the paediatricservicesofahealthdistrictwithhypertransami- nasaemiaintheabsenceofapparentliverdisease.Wemade aseparateevaluationandanalysisofpatientsin whoman aetiological diagnosis was made with the tests or levels requestedinthefirstbloodtestorder.

We wereabletoselectpatientsthroughtheevaluation ofallbloodtestsperformedbytheDepartmentofClinical BiochemistryoftheHospitalUniversitarioMiguelServet in Zaragoza(Spain),whichistaskedwithperformingallblood testsorderedinthehealthdistrict.ThelevelsofALTwere measured withaBeckmanAU5800clinicalchemistryanal- yser(pyridoxal-5-phosphatemethod).

Forthe selectedpatients,we collectedinformationon everybloodtestperformedthereafterandanalysedbyany of the biochemistry departments of the health system of Aragonbyreviewingtheelectronichealthrecords,withthe main goal of assessing the persistence of hypertransaminasaemia, in additiontoassessingother variables suchas cytolysis, cholestasis, liver function and investigation of potentialaetiologies.

Wedefinedadequatefollow-upasperformanceofaddi- tionalbloodtestsuntilabnormallevelsnormalised,or the underlying cause was identified. We defined inadequate follow-up as lack of follow-up testing in the 12 months that followed the initial finding. Clinical practice guide- linesevenrecommendanadditionalfollow-uptestafterthe levelsnormaliseinpatientswithunexplainedhypertransam- inasaemia,asthelevelscouldfluctuate.^3,4Inourstudy,we didnotconsiderabsenceof anewtestafterresolution of elevationinadequatefollow-up.

Weperformed thestatistical analysiswiththesoftware SPSSversion20.0,usingthechisquaretest,Studentttest andanalysisofvarianceanddefiningstatisticalsignificance asap-valueoflessthan0.05.

The studywasapprovedbytheClinicalResearchEthics CommitteeofAragon(CEICA).

Results

Weanalysed572panelswithelevationofALTserumlevels corresponding to403 patients aged 3 months to15 years andperformed in the periodunderstudy.Theyamounted to 8.4% of all ALT tests and 2.9% of all tests analysed by the Departmentof Biochemistry during thesame time period. We excluded 83 patients that had a pre-existing conditionorreceivingtreatmentthatcouldaccountforthe elevation (chemotherapy, neuromuscular disease, chronic liverdisease,immediatepostoperativeperiod,paracetamol poisoning, etc.)and 15asymptomatic patientsundergoing evaluationforhypertransaminasaemiadetectedbeforethe studyperiod.Thus,in305patientstherewasnoapparent causeofhypertransaminasaemia.In69ofthemaprobable aetiological diagnosis couldbemade basedonthe results ofthebloodtestsofadditionaldiagnostictestsperformed atthesametime(infectiousmononucleosisin62.3%,post- infectiousacutemyositisin20.3%,coeliacdiseasein2.9%, etc.).

Clinicalguidelinesrecommendafollow-uptestinthese patients once the episode of intercurrent disease has resolvedtoconfirmnormalisationofthelevels,astheiden- tifieddisease maybe masking an underlyingcondition. In oursample, we found that in thegroup of patientsgiven adiagnosisof acutediseasethatcouldexplaintheaetiol- ogy,normalisationoftheenzymelevelswasonlyobserved followingresolutionofthediseasein33.3%.

Thus, we identified 236 patients without elevation of ALTbeforetheperiodunderstudyandwithoutanapparent healthcondition ortherapeuticintervention priortoor at thetimeoftestingthatcouldjustifyit.Theanalysisincluded thissubsetofpatients.

Of these patients, 47.5% were female (112 patients), and the age distribution was 3.4% aged 3---18 months (8 patients),58.5%aged18monthsto12years(138patients) and38.1%aged12---15years(90patients). Thetestswere orderedatthelevelofprimarycarelevelin55.9%ofcases (132patients),hospital-basedoutpatientcarein33.1%(78 patients),paediatricemergencycarein6.8%(16patients) andinpatientcarein4.2%(10patients).

TheinitiallevelofALTwaslessthantwicetheestablished ULNin75.8%(179patients),betweentwiceand5timesthe ULNin20.3%(48patients)andgreaterthan5timestheULN in3.8%(9patients).

The reason/complaint that led to ordering the initial blood panel was digestive/gastrointestinal in 27.5% (65 patients), acute infection in 16.9% (40 patients), or rou- tine testing that led to an incidental finding in 9.7% (23 patients), preoperative testing with incidental finding in 5.9%(14patients)andotherin39.8%(94patients).

Inoursample,24.57%ofthepatients(58patients)were intreatmentwithadrugprescribedbythepaediatricianin thedaysthatprecededthecollectionofthefirstbloodsam- ple.Themostfrequentdrugsbeingusedwereanti-infective drugs,chieflyoralamoxicillin(18patients),oralamoxicillin- clavulanicacid(12patients)andoralpenicillin(5patients).

Wewereunabletoobtaindataonover-the-countermedica- tion(paracetamol,NSAIDs,coughmedicine,homoeopathic remedies,etc.).

Inadditiontoliverfunctiontests,other measurements or diagnostic tests were ordered for investigation of the aetiologyofhypertransaminasaemia,suchasthyroidfunc- tiontests(48.3%,114patients),markersofcoeliacdisease (27.1%, 64 patients), serum immunoglobulins (22.5%, 53 patients), serological tests (17.8%, 42 patients), abdomi- nalultrasound(11%,26patients),autoantibodies(6.4%,15 patients),ceruloplasmin(4.2%,10patients),serumcopper (3.8%,9patients),alfa-1antitrypsin(3%,7patients),total serum protein (2.5%, 6 patients), reducing substances in urine(0.8%,2 patients),copper in urine(0.4%,1 patient) orDopplerultrasound(0.4%,1patient).

Ofthesepatients,34.3%underwentfollow-uptesting(81 patients),whichrevealedpersistenceofabnormallevelsin 46.8%(37patients).However,in66.5%(157patients)testing wasnotperformedagaininthe12monthsthatfollowedthe abnormalresult.

Whenitcametothetimeelapseduntillaboratorytests were performed for follow-up in patients for who it was requested,itwasof30daysoflessin40.7%(33patients)and greaterthan30daysin59.2%(48patients),withameanof 70.6days(median,46days).Thetimeelapsedtofollow-up

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Adequate followup: 23:

Adequate followup: 69

No follow-up testing: 155 :

Normalization: 58 Liver disease: 9

Persistent elevation: 2 1 followup with blood

tests: 9 572 blood tests

403 patients

Exclusion criteria:

-Pre-existing disease/treatment: 83 -Previous hypertransaminasaemia: 15

305 patients

Diagnosis with the first round of testing: 69 patients

No diagnosis with the first round of testing: 236 patients

Inadequate followup: 46

Normalization: 23

Inadequate followup: 167

2 followups with blood tests: 3

Figure1 Descriptionofpatientselectionandfollow-up.

testing wassignificantly shorter in patients with ALT lev- elsgreaterthantwicetheULN(79.9+66.2days)compared topatientswithlevelslessthantwicetheULN(55.7+63.9 days)andalsoininpatients(75.03+77.3days)comparedto outpatients(66.7+60.3days)(P<.05).

Overall, the follow-up after detection of unexplained hypertransaminasaemiawasnotadequatein70.8%ofcases (167patients).Thus,inoursample,adequatefollow-upwas onlyperformedin29.2%delospatients(Fig.1).

When we analysedthevariables thatcouldexplainthe adequacyorinadequacyofthefollow-up,wedidnotfindan associationbetweenthisvariableandage,sex,thesourceof theorderorthehistoryofpharmacologicaltreatment,but wedidfindanassociationwiththeinitialdegreeofelevation ofALT(Table1).

Inthegroupofpatientswithadequatefollow-up,13%(9 patients)receivedadiagnosisthatexplainedtheelevation ofserumtransaminases.Fourreceivedadiagnosis ofnon- alcoholicfattyliverdisease,2of autoimmunehepatitis,1 ofhepatorenalpolycysticdisease,1ofliverhaemangioma and 1 of hepatic focal nodular hyperplasia. On the other hand, when it came to patients with persistent transaminase elevation, in 2 it was not possible to determine the causeof hypertransaminasaemia during the follow-up despite anexhaustive evaluation(includinga normalliver biopsy)(Table2).

Twothirdsofthepatientsthatreceivedafinaldiagnosis ofliverdiseasehadinitiallevelsofALTlessthantwicethe establishedULN,andwe didnotfindinitiallevelsgreater than5timestheULNinanyofthepatients.

Discussion

Serumelevationofliverenzymesisanincreasinglyfrequent incidental findingin blood tests ordered in asymptomatic patientsor inthecontextof mildsymptoms inthepaedi- atricpopulation.^3,4 This elevationis a nonspecific feature found in numerous conditions, but it may also be the initialclinicalmanifestationofpotentiallyseriousprogres- sive liver disease. Therefore, it is important to monitor these levels to confirm normalisation or to carry out a broaderevaluationtoestablishtheaetiologyoftheeleva- tion.Theaimofourstudywastoanalysethefollow-upin currentclinicalpracticeofpaediatricpatientswithhyper- transaminasaemia in our region. To do so, we selected a 6-monthperiodbackenoughintimetohaveallowedacom- prehensive investigation of hypertransaminasaemia to be completed.

Normal serum liver enzyme levels have not been specifically established in the paediatric population. The thresholdsestablishedinstudiesonthesubjectvarywidely,

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Table1 Variablesunderstudyinthesampleatthetimeofinitialbloodtesting,overallandintheadequateandinadequate follow-upgroups.

Inadequatefollow-up Adequatefollow-up Total P

Ageinyears(mean±SD) 9.48±4.75 8.16±4.95 9.9±4.84 .057

Useofmedication(%) 21.6% 31.9% 24.6% .099

Female(%) 48.5% 44.9% 47.5% .361

ALT<2×ULN(%) 80.8% 63.8% 75.8%(oftotalsample) .01

ALT>2×ULN(%) 18% 26.1% 20.3%(oftotalsample)

ALT>5×ULN(%) 1.2% 10.1% 3.8%(oftotalsample)

Setting^a(PC/HBC) 74.2%/66.3% 25.8%/33.7% 55.9%/44.1% .197

HBC,hospital-basedcare(outpatientcare,emergencycareandinpatientcare);PC,primarycare;SD,standarddeviation;ULN,upper limitofnormal.

a Setting:settingwheretheinitialbloodtestswereordered.

Table2 Patientswithadiagnosisthatexplainedhypertransaminasaemiaorunexplainedhypertransaminasaemiadespiteafull aetiologicalinvestigation.

Diagnosis Age InitialALT

elevation(×ULN)

Reasonforordering Setting Non-alcoholicfattyliver

disease

14years <2 Hypopituitarism

follow-up

Endocrinologyclinic Non-alcoholicfattyliver

disease

9years 2---5 Thalassemia

follow-up

Primarycare Non-alcoholicfattyliver

disease

13years <2 Nonspecificobesity Endocrinologyclinic Non-alcoholicfattyliver

disease

11years <2 Abdominalpain Emergency

department

Autoimmunehepatitis 2years 2---5 Suspectedcoeliac

disease

Gastrointestinalclinic

Autoimmunehepatitis 20months <2 Vomiting Primarycare

Hepatichaemangioma 13years <2 Jointpain Rheumatologyclinic

Hepatorenalpolycystic disease

20months 2---5 Weightfaltering Primarycare

Hepaticfocalnodular hyperplasia

11years <2 Abdominalpain Primarycare

Unexplained

hypertransaminasaemia

6months 2---5 Follow-upof

operated omphalocele

Neonatalcare

Unexplained

hypertransaminasaemia

20months >5 Prolongeddiarrhoea Primarycare

although most proposeadjustments basedonsexand age amongother possiblefactors (ethnicity,countryof origin, laboratory etc.).^7---27 Thus, we believe it is necessary to establishuniversalthresholdstodefinetheneedforfollow- upordiagnosticevaluationadjustedfordifferentvariables, suchasageandsex.

In our study we used the thresholds established by Lamireauetal.,¹⁸ whotookintoaccountthestudiesprevi- ouslyconductedbyEnglandetal.¹⁰andSchwimmeretal.¹¹ Weestablishedanagerangeforthesampleof3monthsto 15years,excludingtheneonatalperiodandconcludingat theagelimitusedtodefineeligibilityforpaediatricservices inthehospitalwherethestudywasconducted.Wedivided thesampleinto3agegroupsbasedonthecriteriaappliedin thecitedstudies:3---18months,18monthsto12yearsand 12---15years.

In our sample, we found a slight predominance of the malesex, which wasconsistent with other studies in the literature.10,13,28---30

Among the multiple reasons for ordering liver functiontests, themost frequent overall are acuteinfectious diseases,asreportedininternationalpublications,^29,30espe- ciallyinpatientswithacutepharyngotonsillitis.Asforthe settingfromwhichtestingisordered,weoughttohighlight theroleofprimarycareinitsinterpretationandinitialfol- low-up, most frequently of a chance finding in otherwise healthypatientswithnonspecificsymptomsorduringarou- tinecheckupinasymptomaticpatients.^1,29,30

The times that must elapsebetween follow-uplabora- torytestsvarydependingontheconsultedguidelines.^3,4,31 Inoursample,themeantimeelapsedtothefirstfollow-up testwas70.6days,andthistimewassignificantlyshorter

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inpatientswithsevereALTelevationandininpatientscom- paredtooutpatients,probablybecausemorebloodtestsare performedoverallinhospitalisedpatients.

We found that 24.5% of patients received some form of pharmacological treatment in the days preceding the initial blood test, usually with an anti-infective agent (chieflyoralamoxicillin,oralamoxicillin-clavulanicacidor oral penicillin), which was consistent with the previous literature.^3,32,33Oneofthelimitationsofourstudywasthat wecouldnotobtain exhaustivedataonthedrugsusedby patients(suchasparacetamol,ibuprofen,mucolyticagents, etc., which can be purchased without a prescription) or their dosage and durationof treatment, which would not bedocumentedinthehealthrecordsofthepatient,orthe useofnaturalornonpharmacologicaltreatmentspotentially associatedwithtransaminaseelevation.

In our study, adequate follow-up of hypertransaminasaemia was performed in less than one third of the patients, anda liverdisease thatexplained theabnormal findings wasidentified in 13% of them. It is possible that someofthepatientsunderwentfollow-uptestinginprivate healthcarefacilitiesorinadifferentautonomouscommu- nity in Spain, although it is fair to assume that if initial testing was performed in a public health care facility in Aragon,thefollow-upwouldalsobeperformedinthepublic healthcaresystemofthisautonomouscommunity.

In our sample, wedid notfind an association between adequatefollow-upandage,sex,settingwheretestingwas ordered or the history of pharmacologicaltreatment, but wefoundagreaterfrequencyoffollow-upinpatientswith higherinitialelevationsofALT,whichsuggeststhatthereisa tendencytounderestimatethesignificanceofmildelevation ofALTasapotentialmarkerofliverdisease.

The obviousconcernraisedbythesefindingsisthepos- sible presence of liver disease in paediatric patients that werenotfollowedupduetotheabsenceornonspecificity oftheirclinicalmanifestationsandthatmaypresent later withprogressiveliverinvolvement,inwhomanopportunity ofdiagnosishasbeenlost.

The lowfrequency offollow-upin oursamplecouldbe due to the lack of agreement between different guide- linesasregardsfollow-upoftransaminaseelevationinthe paediatricpopulation,30,18,28,35---38 inadditiontothelack of consensusonthecut-offpointsusedtointerprettransam- inaselevelsor the potentialmisconceptionin healthcare professionalsthatliverdiseasecanberuledoutinpatients withmildliverenzyme elevation,whichis clearlyrefuted bythefindingsofourstudy.

Other case series in the adult population have found higherproportions of adequate follow-up.Forexample, a study published in 2019³⁴ that analysed the follow-up of hypertransaminasaemia in a sample of adults found that liver function tests had been repeated within a year in 68%ofpatientswithabnormalresultsandwithin2yearsin 80%,andthatfollow-uptestingwasnotperformedfollow- ingthe initialtest resultsinonly 11.7%of thesepatients.

Itisalsoimportanttoconsiderthatintheadultpopulation thereareadditionalfactorsthat couldgiverisetohyper- transaminasaemiaintheabsenceofdisease,mainlyalcohol consumption,whichisnotalwaysdisclosedbypatients,^35,36 andwhich,withexceptionsintheadolescentpopulation,is notatplayinthepaediatricpopulation.

Ourstudydemonstratesthatliverdiseasedoesnotalways manifest withsubstantial transaminase elevation, as two thirdsof thepatientsinoursamplein whoaliverdisease wasidentifiedhadelevated ALTlevelslessthantwicethe ULN.Inthisregard,effortstoimprovecareshouldfocuson ensuringadequatefollow-upofasymptomaticpatientswith mildtransaminaseelevation.

Although many clinical practice guidelines have been published on the subject for the adult population, and several for the paediatric population,3,18---20,35---38 the care protocolsappliedinchildrenand/oradolescentsvarywidely intheappliedcut-offpointsandtheapproachestomanage- ment.Ourintentinconductingthisstudywastounderscore theimportanceoffollow-upineverysinglechildwithhyper- transaminasaemia, independently of age, the degree of liverenzymeelevationortheexposuretopharmacological treatment,ideally followinga standardisedcare protocol.

Needless to say, health care professionals must be made awareoftheimportanceofsuchfollow-up.

Inconclusion,inourhealthcareareaandintheperiod under study, the follow-up of most children with elevation of ALT in the absence of apparent liver disease was inadequate, especially in those with mild elevation. This constitutesamissedopportunityfortheearlydiagnosisand treatmentofpotentialliverdiseaseinalargenumberofchil- dren.Allchildrenwithunexplainedhypertransaminasaemia should undergo evaluation with application of consensus- basedthresholdsandwithastandardisedapproach.

Conflicts of interest

Theauthorshavenoconflictsofinteresttodeclare.

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