• No se han encontrado resultados

Rational application of the new European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2020 criteria for the diagnosis of coeliac disease

N/A
N/A
Protected

Academic year: 2022

Share "Rational application of the new European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2020 criteria for the diagnosis of coeliac disease"

Copied!
9
0
0

Texto completo

(1)

www.analesdepediatria.org

SPECIAL ARTICLE

Rational application of the new European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2020 criteria for the diagnosis of coeliac disease

Enriqueta Román Riechmann

a,∗

, Gemma Castillejo de Villasante

b

, M. Luz Cilleruelo Pascual

a

, Ester Donat Aliaga

c

, Isabel Polanco Allué

d

, Félix Sánchez-Valverde

e

, Carmen Ribes Koninckx

c

aUnidaddeGastroenterologíayNutriciónPediátrica,HospitalUniversitarioPuertadeHierro-Majadahonda,Madrid,Spain

bUnidaddeGastroenterologíaPediátrica,ServiciodePediatría,HospitalUniversitariSantJoandeReus,Reus,Spain

cUnidaddeGastroenterología,HepatologíayNutriciónPediátrica,HospitalUniversitarioyPolitécnicoLaFe,Valencia,Spain

dFacultaddeMedicina,UniversidadAutónomadeMadrid,Madrid,Spain

eUnidaddeGastroenterologíayNutriciónPediátrica,ServiciodePediatría,ComplejoHospitalariodeNavarra,Pamplona,Spain

Received15October2019;accepted5December2019 Availableonline31January2020

KEYWORDS Coeliacdisease;

Diagnosis;

Recommendations;

Serology;

HLA;

Intestinalbiopsy;

ESPGHAN

Abstract Coeliacdiseaseisasystemicimmune-mediateddisordertriggeredbytheingestion ofgluten,whichisgiveningeneticallypredisposedsubjects.Itmanifestswithawidevariety ofclinicalsymptoms,specificserologicalmarkers,HLA-DQ2/DQ8haplotype,andenteropathy.

ThecriteriafollowedforthishaveusuallybeenthoseestablishedbytheEuropeanSocietyfor Paediatric Gastroenterology,HepatologyandNutrition(ESPGHAN)since1969. Thesecriteria haveadvancedfromtheneedofseveralintestinalbiopsiesto,thankstothedevelopmentof serologicaltests ofhighsensitivityandspecificity,consideringtheenteropathyasonemore element inthisdiagnosisandmakesitpossibletoperform adiagnosiswithoutthe needof anintestinalbiopsyincertaincircumstances.Theupdatedreviewofthe2012criteriain2019 providesnewevidenceonsomeaspects,suchastheroleofHLA,thediagnosisofasymptomatic patients,andtheeffectivenessoftheserologicalmarkers.Theseaspectsarereviewedindetail, withtheaimoffacilitatingtherationalapplicationofthenew2020criteriaatallcarelevels.

In this sense,Paediatric Primary Careis fundamentalinthe searchfor active casesand to

Pleasecitethisarticleas:RiechmannER,VillasanteGCd,PascualMLC,AliagaED,AlluéIP,Sánchez-ValverdeF,etal.Aplicaciónracional delosnuevoscriteriosdelaEuropeanSocietyforPaediatricGastroenterology,HepatologyandNutrition(ESPGHAN)2020paraeldiagnóstico delaenfermedadcelíaca.AnPediatr(Barc).2020;92:110.

Correspondingauthor.

E-mailaddress:enriqueta.roman@salud.madrid.org(E.R.Riechmann).

2341-2879/©2019Asociaci´onEspa˜noladePediatr´ıa.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

(2)

performafirstserologicalstudy,beingrecommendedthatthediagnosisisalwaysestablished byaPaediatricGastroenterologist.

©2019Asociaci´onEspa˜noladePediatr´ıa.PublishedbyElsevierEspa˜na,S.L.U.Thisisanopen accessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/

4.0/).

PALABRASCLAVE Enfermedadcelíaca;

Diagnóstico;

Recomendaciones;

Serología;

HLA;

Biopsiaintestinal;

ESPGHAN

AplicaciónracionaldelosnuevoscriteriosdelaEuropeanSocietyforPaediatric Gastroenterology,HepatologyandNutrition(ESPGHAN)2020paraeldiagnósticodela enfermedadcelíaca

Resumen Laenfermedadcelíacaesunprocesosistémicodecarácterinmunológico,desen- cadenado porelconsumode gluten,que sedaensujetosgenéticamentepredispuestos.Se expresaconunagranvariedaddesíntomasclínicos,marcadoresserológicosespecíficos,hap- lotipoHLA-DQ2/DQ8yenteropatía.Eltratamientoconsisteeneliminardeporvidaelglutende ladieta,porloqueesfundamentalundiagnósticoadecuado.Loscriteriosseguidosparaello hansidohabitualmentelosestablecidosporlaEuropeanSocietyforPaediatricGastroenterol- ogy,HepatologyandNutrition(ESPGHAN)desde 1969.Estoscriterios hanidoevolucionando desdelanecesidaddevariasbiopsiasintestinalesparaeldiagnósticoa,graciasaldesarrollo depruebasserológicasdealtasensibilidadyespecificidad,considerarlaenteropatíacomoun elementomásenestediagnósticoyposibilitar endeterminadascircunstanciasrealizarlosin necesidaddebiopsiaintestinal.Larevisiónactualizada en2019deloscriterios2012aporta nuevaevidenciasobrealgunosaspectos,comoelpapeldelHLA,eldiagnósticodelospacientes asintomáticosylaeficaciadelosmarcadoresserológicos.Estosaspectosserevisanendetalle, conelobjetivodefacilitarlaaplicacióndelosnuevoscriterios2020deunaformaracionalen todoslosnivelesasistenciales.EnestesentidoelpediatradeAtenciónPrimariaesfundamental paralabúsquedaactivadecasosyrealizarunprimerestudioserológico,recomendándoseque eldiagnósticoseasiempreestablecidoporunpediatragastroenterólogo.

© 2019Asociaci´on Espa˜nola dePediatr´ıa. Publicado por Elsevier Espa˜na, S.L.U.Este es un art´ıculoOpenAccessbajolalicenciaCCBY-NC-ND(http://creativecommons.org/licenses/by- nc-nd/4.0/).

Definition of coeliac disease

BasedonthemostrecentdefinitionoftheEuropeanSociety for Paediatric Gastroenterology, Hepatologyand Nutrition (ESPGHAN),1 coeliac disease (CD) is an immune-mediated systemicdisorderelicitedbytheconsumptionofglutenand relatedprolamins(secalins,hordeinsandpossiblyavenins) in genetically susceptible individuals (human leukocyte antigen[HLA]haplotype).Itmanifestswithavariablecom- binationofclinicalsymptoms,specificserologicalmarkers, aHLA-DQ2/DQ8haplotypeandenteropathy.

Treatment consistsinthe life-longstrictelimination of gluten fromthe diet, which achieves resolution of symp- toms, negative titres of autoantibodies and histological recoveryoftheintestinalmucosa.

Evolution of diagnostic criteria

In 1969, the ESPGHAN established the first stringent cri- teriafordiagnosis of CDin thepaediatric population,the so-calledInterlakencriteria2(Table1).Theyestablishedas mandatorycriteriaevidenceofvillousatrophyintheinitial intestinalbiopsy(IB)whilethepatientconsumesagluten- containingdiet, histological recovery after elimination of glutenandrecurrenceofthelesionafterglutenreintroduc-

tion(challengetest)todifferentiateCDfromother causes ofenteropathy.

Theapplicationofthesecriteriaalongwiththediscov- eryintheearly1980sofamarkerofactiveCD,antigliadin antibodies(AGAs),3promptedtheirrevision,leadingtothe establishmentofthenew1990ESPGHANcriteriafordiag- nosisof CD.4These criteriaallowedmakingthediagnosis in older children with symptoms suggestive of CD after a single IB withcharacteristic (albeitnonspecific) abnormal mucosalhistologyinthecontextofagluten-containingdiet andimprovementofsymptomswithexclusionofglutenfrom thediet.Theglutenchallengewastobereservedforchil- drenagedlessthan2yearsatthetimeoftheinitialIB,cases diagnosedwithoutanIBandcasesofuncertaindiagnosis.

Endomysial antibodies (EMAs)5 were discovered in the mid-1980s,andtissuetransglutaminase(tTG)wasidentified in1997astheautoantigenofCD,followedbythediscovery of thepresence of circulatinganti-tTG type2antibodies.

Bothtypesofantibodieshadasimilarsensitivityandspeci- ficity and performed better asmarkers of active CD than AGA.6

The21stcentury:anewscenario

The 1990 ESPGHAN criteria continued to be in use until numerous studies demonstrated the excellent correlation

(3)

Table1 EvolutionofESPGHANcriteriafordiagnosisofCD.1,2,4,13

1969criteria 1990criteria 2012criteria 2020criteria

•3IBsrequiredfordiagnosis. •AtleastoneinitialIBis necessaryfordiagnosis.

•Insymptomaticpatients withananti-tTGIgAtitre

>10xULN,positiveEMA(in asecondserumsample)and HLADQ2/DQ8,CDcanbe diagnosedwithoutthe initialIB.

•Insomeasymptomatic patientsmeetingthe establishedcriteria,the diagnosisofCDcanbemade omittingtheinitialIB.

•Glutenchallengetest requiredinalmostevery case.

•Theglutenchallengetest isrequiredinallchildren agedlessthan2yearsorin caseofuncertaindiagnosis.

•Theglutenchallengetest isonlyrequiredincaseof uncertaindiagnosis.

•HLAtestingisnot necessaryfortheno-biopsy diagnosis.

InpatientswithIgA deficiencyorT1D,IBis required.

Timeelapsedtoconfirmationofdiagnosisbasedontheappliedcriteria:

•Inallcases,diagnosisis confirmedafter5---6yearsof followup.

•Inmostchildren,diagnosis isconfirmedafter5---6years offollowup.

•Inmostcases,diagnosisis confirmedafter1---3months offollowup.

•Inmostcases,diagnosisis confirmedafter1---3months offollowup.

CD,coeliacdisease;EMA,endomysialantibodies;IB,intestinalbiopsy;T1D,type1diabetesmellitus;tTG,tissuetransglutaminase;ULN, upperlimitofnormal.

betweenanti-tTGantibodytitresandthedegreeofvillous6,7 andthestrongperformanceofEMAtitresforpredictionof futurelesions.8Thisledtoquestioningtheroleofthetra- ditional histological examination asthe gold standard for diagnosis of CD8,9 and the need for a gluten challengein childrenagedlessthan2years,asmostofthosewithvillous atrophyandpositiveEMAtitresexperiencedarecurrenceof symptomswiththechallenge.9

Asaresultofthegatheredevidence,thenewESPGHAN guidelines for the diagnosis for Coeliac Disease in chil- drenand adolescents.Anevidence-based approach1 were published in 2012,with a novel definitionof CD in which enteropathy was just one of the elements to considerin the diagnosis, and not a requisite criterion. The guide- linescontemplateddiagnosiswithoutperformanceofanIB incertain cases(suggestivesymptoms,high titres ofanti- tTGantibodies,positiveEMAantibodiesinasecondsample and compatibleHLA haplotype). Evidencefrom the years thatfollowedconfirmedthatdiagnosiswithoutabiopsywas safeinthesecases,10---12 andthelatestupdateofthe2012 guidelines, published in 2020, presents new evidence on certainaspectsofCD,suchastheroleofHLA,thediagno- sisofasymptomaticpatientsandtheefficacyofserological markers.13 Wewillnowreviewtheseaspectsindetailwith theaim offacilitatingtherational applicationof thenew 2020criteriaintheoutpatientandinpatientsettings.

Role of clinical manifestations

ClinicalsignsandsymptomsassociatedwithCD(Table2)are thefeaturesthat,onappearing,leadtosuspicionofCDand theneedfordifferentialdiagnosis.

The information available on the clinical presentation of CD hasexperienced drastic changes withthe develop- mentofhighlysensitiveandspecificserologicaltests.New

Table 2 Situations in which CD should be investigated (adaptedfromtheESPGHAN2020guidelines).13

Inchildrenandadolescentswithanyofthefollowing symptomsiftheaetiologyisunknown:

•Gastrointestinalsymptoms:

Chronicorintermittentdiarrhoea Abdominaldistension

Recurrentnauseaorvomiting Chronicabdominalpain Chronicconstipation

•Extraintestinalsymptoms

Failuretothrive,weightloss,stuntedgrowth Iron-deficiencyanaemia

Abnormalresultsofliverfunctiontests Recurrentaphthousstomatitis

Shortstature

Delayedpuberty,amenorrhoea Dermatitisherpetiformis Chronicfatigue,irritability

Bonefracturefrommildtrauma/osteopenia/osteoporosis Neuropathy

Arthritis,arthralgia Dentalenameldefects

Inchildrenandadolescentsbelongingtoanyofthe followingat-riskgroups:

•First-degreerelativewithCD

•DiabetesmellitustypeI

•Autoimmunethyroiddisease

•Autoimmuneliverdisease

•Downsyndrome

•Turnersyndrome

•Williamssyndrome

(4)

categoriesofpatientshavebeen identifiedthat havemild gastrointestinal symptoms, symptoms considered atypical (extraintestinalmanifestations)ornosymptoms,aswellas factorsthatincreasetheriskofCD,whichhasledtochanges intheclinicalformsofdiseasecurrentlydiagnosed,withan increase in atypical and silent forms. Coeliac diseasehas gonefrombeing considered a paediatric diseaseto being diagnosedthroughoutthelifespan.14

Whenitcomestothespecificityofitsfeatures,arecent studyinacohortofpatientswithpositiveserologicaltests forCD found thatthecombination of aclinical pictureof malabsorption (chronic diarrhoea, weight loss, failure to thriveand anaemia)and high titres of specific antibodies (anti-tTGantibody titre>10 timestheupperlimitof nor- mal[ULN]andapositive EMAresult)hada 100%positive predictivevalue for intestinalinvolvementcomparedtoa slightly lowervalue ifthe antibody titres were combined withsymptomsotherthanmalabsorption.12

Screening for CD should also be performed in spe- cific situations that carry an increased risk for it, such as autoimmune disease, certain chromosomal disorders, IgA deficiency and historyof CD in a first-degree relative (Table2).13

Ontheother hand,thenotionofuniversalscreeningin thegeneralpopulationremainscontroversial,asCDdoesnot fulfilthecriteriaestablishedbytheWorldHealthOrganiza- tionforscreeningtests.Differentgroupsofexpertssupport therecommendationoftheESPGHANofactivecasefinding, giventhelackofevidenceontheoutcomesofasymptomatic patientsthatdonotreceiveadiagnosis.15,16

Role of serology

Giventhehighaccuracyoftheantibodytestsusedfordiag- nosisof CD,serologicaltesting isrecommendedfor initial screeningofpatientswithsuspectedCD.

Antitransglutaminaseantibodies

TheinitialtestintheevaluationofCDshouldbetheanti-tTG antibodytestonaccountofitshighsensitivityandspecificity aswellasitswideavailabilityandtheuseofanautomated andobjectivemethod(enzymeimmunoassay).Arecentsys- tematicreviewwithmeta-analysis16 found a sensitivityof 92.8% (95% confidence interval[CI],90.3 %---94.8 %)and aspecificity of 97.9% (95 % CI,96.4 %---98.8%). Titres of anti-tTGIgAgreaterthan10timestheULNpredictthepres- enceofvillouslesionswithahighspecificity.17 Therehave beenreportsofoccasionalfalsepositiveresults,usuallyat lowtitres, due tocross-reactivitywithantibodies present inother clinicalconditions,suchasautoimmunediseases, liverdiseasesorinfections.18

Endomysialantibodies

Endomysial antibodies react with the endomysium, the perivascularconnectivetissuethatlinessmoothmusclebun- dles.Theytargettransglutaminaseintissuessuchasmonkey oesophagusorumbilicalcordtissue,whichareusedassub- stratesinthetestsdeveloped fortheirmeasurement.The

diagnosticaccuracyofEMAIgAisveryhigh,19withahighsen- sitivityandspecificity.13Themaindrawbackofthismarker isthatitismeasuredbymeansofindirectimmunofluores- cence, a semiquantitative and subjective method that is moreexpensive,requiresexperiencedstaffandtakeslonger thanthemeasurementofanti-tTGantibodies.

Antibodiesagainstdeamidatedformsofgliadin peptides

Gliadinpeptidesaredeamidatedbytissuetransglutaminase, whichresultsinasignificantincreaseintheirimmunogenic- ity.Thisinspiredthedevelopmentofmethodsfordetection of deamidated gliadin peptide (DGP) antibodies, which have sincereplacedpreviously usedtestsfordetection of antigliadinantibodies.OneadvantageofDGPantibodies is that they are detected by an objective method, enzyme immunoassay. The sensitivityof DGPIgA and IgGantibod- iesis87.8%(95%CI,85.6%---89.9%)and94.1%(95%CI, 92.5%---95.5%),respectively.16TestingforDGPIgGantibod- iesisusefulfor evaluationofCDinpatientswithselective IgA deficiency.20 However,theyield is lower comparedto positiveanti-tTGIgAtitresandisolatedpositiveDGPresults maygiverisetofalsepositivesthatincreasethefrequency ofunnecessaryendoscopies.21---23

Rapidtests

They areperformed bymeans of immunochromatography, and therefore arenot quantitative. They involveapplica- tionoffewdropsofcapillarybloodonasolidsupport,and astheblooddiffusesthroughthematrixalinebecomesvis- ibleinthetest windowiftheresultispositive.Thereare rapidtestsfordetectionofanti-tTGtype2,AGAoracombi- nationofseveralantibodies.Thesetestshavebeenusedfor non-invasivescreeningofCDandexhibitedagoodcorrela- tionwithstandardserologicaltestsaslongasthetestsare interpretedbyadequatelytrainedstaff.Thesensitivityand specificityofthesetestsare94.0%(95%CI,89.9%---96.5%) and94.4%(95%CI,90.9%---96.5%)respectively,although currentlytherearenotenoughdatatosupporttheirusein everydayclinical practice,sotheirresultsmust alwaysbe confirmedbystandardserologicaltesting.24

Limitationsofserologicaltests

Althoughthemeasurementofanti-tTGIgAantibodiesisnot standardised,mostcommerciallyavailabletestsarehighly accurate,especiallyathightitres.25However,thereisevi- dence of variability between different tests or different laboratoriesusingthesametestwhenitcomestomoderate anti-tTGtitres.12 Laboratories mustbeextremely rigorous intheirinternalqualitycontrolmeasures,accuratelycalcu- latingthecalibrationcurve,whichshouldincludethevalue of10timestheULN.13

Serologicaltestingmustbeperformedwhilethepatient continues toconsume gluten, asantibody titres decrease after initiation of a low-gluten or gluten-free diet. If a patientwasonagluten-restricteddietduringthediagnos- ticevaluation,expertsrecommendconsumptionofanormal

(5)

dietincludingatleast3slicesofbreadadayfor1---3months tothenrepeatthemeasurementofanti-tTGantibodies.26

The initialanti-tTGIgA measurementshouldbeaccom- panied by measurement of total serum IgA and, in case ofdetectionofselectiveIgAdeficiency,thepatientshould befurtherevaluatedwithperformanceofanti-tTG,EMAor PDGIgGtests.1,13Incontrasttoanti-tTGIgAtitres,nostud- ieshavebeenconductedtoestablishthelevelsofanti-tTG IgGthatcanreliablypredictthepresenceof enteropathy.

Thus,performance of an IB isnecessary in thesechildren to confirm the diagnosis.13 Other possible causes of false negatives are immunosuppressive therapy and dermatitis herpetiformis, usually associated with negative serology.

Measurement in haemolysedspecimens mayalsoreflect a falsedecreaseinantibodytitres.27

The evidenceis alsoinsufficientasregardsthecorrela- tionofhighanti-tTGtitreswiththepresenceofenteropathy in children with type 1 diabetes (T1D). In addition, high titres ofanti-tTGantibodies havebeen describedin stage 1 of T1D with spontaneous normalization of CD serology at moderatetitres,28,29 soperformanceof an IBis recom- mendedfordiagnosisofCDinthesepatients.

Role of genetic testing

Coeliacdiseaseisassociatedwithaspecifichigh-risk vari- ants of the HLA class II region, whose alleles encode molecules involved in the presentation of gluten peptide antigenstoCD4+Tcells,thusplayingaroleintheimmune cascadethatresultsinglutenintolerance.Morethan90%of patientswithCDarefoundtobehomozygousorheterozy- gous for the HLADQ2.5 variant encoded by the DQA1*05 (␣-chain) andDQB1*02(␤-chain) genes.The isolatedHLA- DQ2.2haplotype(DQA1*02-DQB1*02) carriesamuchlower risk, for while the resulting heterodimer is homologous to the DQ2.5 heterodimer it forms less stable complexes withthepeptides.PatientsthatdonothavetheDQ2type havetheDQ8type,encodedbytheDQA1*0301-DQB1*0302 alleles.1Thereareseveralcombinationsofthe2allelesthat carryaspecificriskof developingCD.30 ClassII HLAgenes accountfor40%ofthegeneticriskofCD,whileotherparts ofthegenomehavebeenshowntohaveaninfluenceofless than 10%.31 Inrecent years,the complexityof the inter- pretationofHLAtypinghasledtoeffortstostandardisethe nomenclature.32

High-riskHLAhaplotypesarerelativelyfrequentinsome populations,whichisassociatedwithahigherincidenceof CDifconsumptionofwheatandothergrassesiscustomary inthepopulation,asisthecaseinSpain.30Inthissense,HLA genotypingisoflittleusefordiagnosis,asithasaverylow positive predictive value. However,its high negative pre- dictivevalue makesitveryusefulin rulingoutCD incase ofuncertaindiagnosisandtoestablishtheriskofdevelop- ingCD inpopulationgroups withahigh prevalenceof the disease.12,19,33,34

Recent studieshavereportedthatnearly100%ofindi- viduals with anti-tTG antibody titres above 10 times the ULN, apositive EMAresultand an abnormalmucosahave aDQ2/DQ8haplotype,whichmeansthatHLAtypingwould notbenecessarytoconfirmthediagnosiswithoutanIB,12,19

asonlyindividuals withDQ2/DQ8 haplotypes canproduce theseantibodies.35

Duetoalloftheabove,itseemsreasonabletoconsider thattheinterpretationoftheHLAhaplotypeandtheassoci- atedriskisjustoneamongmanytoolsinthemanagementof CDandneedstobeperformedbypaediatriciansspecialised inpaediatric gastroenterology andwithexperiencein the managementofCD,1,13andthereforewedonotrecommend HLAgenotyping for initial screening of CD at the primary carelevel.

Role of intestinal biopsy

Anintestinal biopsy is nolonger required for diagnosis of CDineverypatient,1 butitunarguablycontinuestobean essentialtool.

The interpretation of histological findings poses some challenges and therefore may vary between pathologists.

Tooptimisetheanalysisoftheintestinalmucosa,werecom- mendobtainingseveralbiopsysamplesthroughendoscopy, withatleast4specimensofduodenalmucosaand1ofthe duodenal bulb, asin some casesthis is the only affected area.1,13

Astandardisedprotocolmustbeusedtoobtaincorrectly oriented cuttings of duodenal tissue. A villus height and cryptdepthratiooflessthan2inat least1ofthebiopsy samplesisconsidereddiagnosticofCD.36 Theschemeused mostwidelytoclassifythedegreeofmucosalinjuryisthe MarshclassificationmodifiedbyOberhüber37(Table3).The diagnosisof CDrequires thepresenceof Marsh2 or3 his- tological changes, although no degree of enteropathy is pathognomonic.

Itisimportanttoincludethefollowinginformationinthe pathologyreport:

• Whethertheamountoftissueinthesamplewassufficient

• Whetherthe specimenswerewellorientedandallowed assessmentofvillousheight

• Percentageof intraepitheliallymphocytes(IELs)in rela- tiontothetotalepithelialcellcount

• Presenceofabsenceofcrypthyperplasia(mitosis)

• Degreeofvillousatrophy.

The presence of Marsh 1 changes (a density of more than 25 IELs per 100 epithelial cells) is not sufficient to diagnoseCD,asthisamountofinjurycanbeattributedto other causes, suchas foodallergy, infection (viralaetiol- ogy,Giardia,Cryptosporidium,Helicobacterpylori),drugs, autoimmune disease, inflammatory bowel disease, etc.38 Mild changes can also be found in patients with possible CD(patients with mild Marsho or 1 changesand positive anti-tTG and EMA results combined with a high-risk HLA haplotype),in whom prescription of a gluten-free diet is controversial.39 Inthesecases,itmaybeusefultoanalyse thecytometricpatternofIELsubpopulations(elevationof CD3+TCR␣␤ Tcells associatedwitha decreasein NK-like cells)orthepresenceofanti-tTGantibody depositsinthe mucosa.13,39

The abovenotwithstanding, insomecasesthereis still disagreementbetweentheresultsofanti-tTGantibodytest- ingandhistologicalfindings.Insuchcases,werecommend

(6)

Table3 Marsh---Oberhüberclassification.37

Stage0Preinfiltrative Histologicallynormalmucosa

Stage1Infiltrative IncreasedIELswithpreserved

villousarchitecture

Stage2Hyperplastic Hyperplasticcryptsand

increasedIELs

Stage3Destructive Villousatrophywith

hyperplasticcryptsand increasedIELs

SubdivisionstablishedbyOberhüber basedonthedegreeofVA:

3apartialVA 3bsubtotalVA 3ctotalVA

Stage4Hypoplastic Irreversiblevillousatrophy Doesnotrespondtogluten-freediet, screenforestablishmentofmalignant T-cellcloneintheintestinaltract.

IEL,intraepitheliallymphocyte;VA,villousatrophy.

a histological re-evaluation by examination of additional biopsyspecimensorgettingasecondopinionfromanexpert pathologist.13

European Society for Paediatric

Gastroenterology, Hepatology and Nutrition 2012 criteria

In light of the excellent correlation found between anti- tTG and EMA IgA antibody test results and the presence ofmucosalchanges,the2012ESPGHANguidelines1allowed thepossibilityofdiagnosingCDwithoutanIBexclusivelyin patientsmeetingthefollowingcriteria:

• Suggestivesymptoms

• Anti-tTGIgAtitresgreaterthan10timestheULN

• PositiveEMAIgAtest,whichhasthehighestspecificity,in asecondserumsampletoconfirmthediagnosisandmin-

imisetheimpactofpotentialmethodologicalorlabelling errorsintheinitialmeasurementofanti-tTGIgAtitres.

• CompatibleHLA-DQhaplotype(DQ2and/orDQ8).

Theaccuracyofthisapproachwasconfirmedin2large- scale studies published in 2017.12,19 In everyday clinical practice,thisapproachpreventsatleast35%ofIBs,mainly inchildrenagedlessthan5yearsandinpatientswithsig- nificantsymptoms.40

Inrecent years,therole ofserological testingand the 2012ESPGHANcriteriafordiagnosisofCDhasbeenanalysed inscenariosotherthanthesymptomaticpatient.Evidence hasemergedthatanti-tTGIgAtitresgreaterthan10times theULN predictthepresence ofmucosalinjury inasymp- tomatic patients, although the positive predictive value of this finding may be lower compared to symptomatic patients.12,13

(7)

Table4 CorerecommendationsoftheESPGHANfordiagnosisofCDinchildrenandadolescents;2012and2020guidelines.1,13

•CDshouldbesuspectedinchildrenpresentinganyofthesigns,symptomsofriskfactorslistedinTable2.

•ThefirststepindiagnosisismeasurementofserumlevelsoftotalIgAandanti-tTGIgAantibodies.

•IntheabsenceofCDantibodies(anti-tTGorEMA),theprobabilityofCDinchildrenisextremelylow

•ThediagnosisofCDcanbeestablishedwithoutanIBinchildrenandadolescentswithsymptomssuggestiveofCEandan anti-tTGIgAtitre>10×ULNconfirmedbyapositiveEMAtest(inasecondsample)inapaediatricgastroenterologyunit.

•Thesameno-biopsydiagnosticprotocolmaybeappliedtoasymptomaticchildren,butthismustbeconsideredindividually ineachcasemustinapaediatricgastroenterologyunit.

•InasymptomaticchildrenwithIgAdeficiencyorT1D,anIBisrequiredtoconfirmthediagnosis.

•IndividualswithHLAhaplotypesotherthanDQ2/DQ8haveaverylowriskofdevelopingCD.HLAtestingisnotrequiredto makethediagnosiswithoutanIBinpatientswithananti-tTGIgAtitre>10×ULNconfirmedbyapositiveEMAtest.HLA typingisindicatedforscreeninginindividualswithriskfactorsoranuncertaindiagnosis.

CD,coeliacdisease;EMA,endomysialantibodies;IB,intestinalbiopsy;T1D,type1diabetesmellitus;tTG,tissuetransglutaminase;ULN, upperlimitofnormal.

Clinical suspicion of CD

Measure serum anti-tTG IgA and total IgA1

CONFIRMED CD Refer to paediatric gastroenterologist2

Test for EMA CD risk group Positive CD serology

no anti-tTG test (rapid test or DGP)

tTG IgA & total IgA

Review the results of initial anti-tTG IgA antibodies

Repeat if previous test performed with rapid or qualitative test

Discuss diagnostic pathways with the family3

Anti-tTG IgA < 10 ULN4

BIOPSY

EMA IgA

Negative EMA IgA

PAEDIATRIC GASTROENTEROLOGY Negative anti-tTG IgA

Anti-tTG IgA ≥10 x ULN Positive anti-tTG IgA

Positive EMA

PRIMARY CARE

Consider anti-tTG IgA titre (x ULN)

Marsh 2-3 Marsh 0-15 Consider the risk of false negative serology :

IgA deficiency

Low gluten intake

Immunosuppressive therapy

Extraintestinal manifestations (dermatitis herpetiformis)

Risk of false negative serology

Yes No

No CD

Figure1 Diagnosticalgorithm(adaptedfromESPGHAN202013).

1.IgAdeficiency:valuesbelowthethresholdsestablishedbythelaboratoryforageor<0.2g/Linchildrenagedmorethan3years.

2.Askthefamilynottoinitiatealow-glutenorgluten-freedietbeforethepatientisevaluatedinthePaediatricGastroenterology department.

3.Conveythemessagethatregardlessofhowthediagnosisisreached,treatmentwithagluten-freedietislife-long.

4.Incaseofapositiveanti-tTGIgAtestwithalowtitre,confirmsufficientdietaryglutenintake.Considerrepeatingserological testsaddingtheEMAtest.

5.Consider:a.revisionofbiopsyresults;b.falsepositiveanti-tTGresultandtestingforEMA(ifpositiveEMA=potentialCD);c.

additionaltests(HLA,anti-tTGdeposits,cytometry,etc);d.considerfollowupandretestingensuringnormalglutenintake;e.assess therelevanceofsymptoms.

tTG=tissuetransglutaminase antibodies,EMA=endomysialantibodies;DGP=deamidatedgliadinpeptideantibodies,ULN=upper limitofnormal.

(8)

Table5 ConsequencesoferrorsinthediagnosisofCD.41

Underdiagnosis(maintenanceofgluteninthediet) Overdiagnosis(unnecessaryeliminationofgluten) Impactonqualityoflifeduetopersistentsymptoms Impactonqualityoflifeofpatientandfamily Riskofimpairedgrowthanddevelopment Economicimpact

Long-termcomplications: Riskofimbalanceddiet:potentialdeficienciesinvitaminsand traceminerals

Reproductiveproblems/osteopenia Riskofconstipationandoverweight Gastrointestinalmalignancy

Autoimmunedisease

Updated 2020 criteria

Duetoalloftheabove,the2020guidelines13:

• Confirmthat theinitial evaluation ofCD shouldinvolve measurementofanti-tTGIgAandtotalserumIgAlevels.

IncaseofIgAdeficiency,thesecondstepshouldbetesting forIgGantibodies.

• Allow the option of diagnosing CD in asymptomatic patientswithout an IBfollowing thesamestepsusedin symptomaticpatients.However,sincethepositivepredic- tivevalueofhighanti-tTGtitresislowerinasymptomatic patients, the decision to use the no-biopsy approach should be made on a case-by-case basis and with the agreement of the parents and also the patient if age allows.

• Donotallowtheno-biopsyapproachfordiagnosisofCD inasymptomaticpatientswithT1D,asthescientificevi- denceinthispatientsubsetiscurrentlyinsufficient.

• MaintaintheneedforanIBinpatientswithIgAdeficiency due to the lack of dataon the predictive value of IgG antibodiesforthepresenceofmucosalinjury.

• Establish that HLA genetic testing is unnecessary in patients that require an IB or with anti-tTG IgA titres greater than10times theULN.This test wouldonlybe indicatedfor screeningofat-riskindividualsandincase ofuncertaindiagnosis.

Current situation

The evolution of the ESPGHAN criteria for diagnosis of CD a in the past 50 years has led to the current recom- mendations, with7 core recommendations (Table 4). The processtofollowincaseofsuspectedCDorpresenceofrisk factorsissummarisedinadiagnosticalgorithm(Fig.1).Pri- marycarepaediatriciansplayanessentialroleinsuspecting thediagnosisandorderingtheinitialserologicaltests.The ESPGHANrecommendsthatthediagnosisalwaysbemadeby apaediatric1,13giventhatadiagnosisofCDinvolvesthepres- criptionofagluten-freedietforlife,and,inmostcases,the diagnosisisconfirmedwithinashorttimeframe,allwiththe ultimatepurposeofavoidingbothoverdiagnosisandunder- diagnosisandtheirconsequences(Table5).41Attheprimary carelevel,thiscallsformaintenanceofagluten-containing dietuntilthediagnosisisconfirmed.

Conflict of interest

Theauthorshavedeclarednoconflictsofinterest.

References

1.HusbyS,KoletzkoS,Korponay-SzaboIR,MearinML,PhillipsA, ShamirR,et al. forthe ESPGHANWorking Groupon Coeliac DiseaseDiagnosis, onbehalf of theESPGHAN Gastroenterol- ogy Committee. ESPGHAN guidelines for the diagnosis for CoeliacDiseaseinchildrenandadolescents.Anevidence-based approach.JPediatrGastroenterolNutr.2012;54:136---60.

2.MeeuwisseGW.Diagnosticcriteriaincoeliacdisease.ActaPae- diatrScand.1970;59:461---3.

3.Ribes-KoninckxC,GiliamsJP,PolancoI,Pe˜naAS.IgAantigliadin antibodiesinceliacandinflammatoryboweldisease.JPediatr GastroenterolNutr.1984;3:676---82.

4.Walker-SmithJA,GuandaliniS,SchmitzJ,ShmerlingDH,Visako- rpiJK.Revisedcriteriafordiagnosisofcoeliacdisease.Report ofworkinggroupofESPGAN.ArchDisChild.1990;65:909---11.

5.Rossi TM, Slbini CH, Kumar V. Incidence of celiac disease identified by the presence of serum endomysial antibodies in children with chronic diarrhea, short stature, or insulin- dependentdiabetesmellitus.JPediatr.1993;123:262---4.

6.Barker CC, Mitton C, Jevon G, Mock T. Can tissue trans- glutaminase antibody titers replace small-bowel biopsy to diagnoseceliacdiseasein selectpediatricpopulations? Pedi- atrics.2005;115:1341---6.

7.DahlbomI, Korponay-SzabóIR,Kovács JB, SzalaiZ, Mäki M, Hansson T. Prediction of clinical and mucosal severity of coeliacdiseaseanddermatitisherpetiformisbyquantification ofIgA/IgGserumantibodiestotissuetransglutaminase.JPedi- atrGastroenterolNutr.2010;50:140---6.

8.KurppaK,AshornM,IltanenS,KoskinenLL,SaavalainenP,Kosk- inenO,etal.Celiacdiseasewithoutvillousatrophyinchildren:

aprospectivestudy.JPediatr.2010;157:373---80.

9.Ribes-Koninckx C, Mearin ML, Korponay-Szabó IR, ShamirR, HusbyS,VenturaA,etal.ESPGHANWorkingGrouponCoeliac DiseaseDiagnosis.Coeliacdiseasediagnosis:ESPGHAN1990cri- teriaorneedforachange?Resultsofaquestionnaire.JPediatr GastroenterolNutr.2012;54:15---9.

10.KlappG,MasipE,BolonioM,DonatE,PoloB,RamosD,etal.

Coeliacdisease:thenewproposedESPGHANdiagnosticcriteria doworkwellinaselectedpopulation.JPediatrGastroenterol Nutr.2012;56:251---6.

11.DonatE, RamosJM,Sánchez-ValverdeF,Moreno A, Martinez MJ,LeisR,etal.SEGHNPWorkingGrouponCoeliacDisease.

ESPGHAN 2012 Guidelinesfor Coeliacdisease diagnosis: val- idation througha retrospective Spanishmulticentricstudy.J PediatrGastroenterolNutr.2016;62:284---91.

12.Werkstetter KJ, Korponay-Szabó IR, Popp A, Villanacci V, SalemmeM,HeiligG,etal.ProCeDEstudygroup.Accuracyin

(9)

diagnosisofCeliacdiseasewithoutbiopsiesinclinicalpractice.

Gastroenterology.2017;153:924---35.

13.Husby S, Koletzko S, Korponay-Szabó I, Kurppa K, Mearin ML, Ribes-Koninckx C, et al. European Society Paediatric Gastroenterology,HepatologyandNutritionGuidelinesfordiag- nosing Coeliac disease 2020. J Pediatr Gastroenterol Nutr.

2020;70:141---56.

14.LudvigssonJF,MurrayJA.EpidemiologyofCeliacdisease.Gas- troenterolClinNorthAm.2019;48:1---18.

15.LudvigssonJF,CardTR,KaukinenK,BaiJ,ZingoneF,Sanders DS,etal.Screeningfor celiacdiseaseinthegeneralpopula- tionandinhigh-riskgroups.UnitedEuropeanGastroenterolJ.

2015;3:106---20.

16.ChouR, Bougatsos C,Blazina I,Mackey K, Grusing S, Selph S.ScreeningforCeliacdisease: evidencereportandsystem- aticreviewfortheUSPreventiveServicesTaskForce.JAMA.

2017;31:1258---68.

17.HillPG,HolmesGK.Coeliacdisease:abiopsyisnotalwaysnec- essaryfordiagnosis.AlimentPharmacolTher.2008;27:572---7.

18.Ferrara F,Quaglia S, Caputo I,Esposito C, Lepretti M, Pas- toreS,etal.Anti-transglutaminaseantibodiesinnon-coeliac childrensufferingfrominfectiousdiseases.ClinExpImmunol.

2010;159:217---23.

19.WolfJ,PetroffD,RichterT,AuthMKH,UhligHH,Laass MW, et al. Validation of antibody-based strategies for diagnosis ofpediatric celiacdisease without biopsy.Gastroenterology.

2017;153:410---9.

20.VillaltaD,TonuttiE,PrauseC,KoletzkoS,UhligHH,Vermeersch P,etal.IgGantibodiesagainstdeamidatedgliadinpeptidesfor diagnosisofceliacdiseaseinpatientswithIgAdeficiency.Clin Chem.2010;56:464---8.

21.HoerterNA,ShannahanSE,SuarezJ,LewisSK,GreenPHR,Lef- flerDA,etal.Diagnosticyieldofisolateddeamidatedgliadin peptide antibody elevation for Celiac disease. Dig Dis Sci.

2017;62:1272---6.

22.GouldMJ,BrillH,MarconMA,MunnNJ,WalshCM.Inscreening forCeliacdisease,deamidatedgliadinrarelypredictsdisease whentissuetransglutaminaseisnormal.JPediatrGastroenterol Nutr.2019;68:20---5.

23.BishopJ,ReedP,AustinP,HurstM,AmeratungaR,CraigieA, etal. Prospectiveevaluation ofthe ESPGHAN Guidelinesfor DiagnosisofCeliacDiseaseinNewZealandChildren.JPediatr GastroenterolNutr.2018;67:749---54.

24.SinghP,AroraA,StrandTA,LeoflerDA,MäkiM,KellyCP,etal.

Diagnosticaccuracyofpointofcaretestsfordiagnosingceliac disease:asystematicreviewandmeta-analysis.JClinGastroen- terol.2019;53:535---42.

25.VermeerschP,GeboesK,MariënG,HoffmanI,HieleM,Bossuyt X.Definingthresholdsofantibodylevelsimprovesdiagnosisof celiacdisease.ClinGastroenterolHepatol.2013;11:398---403.

26.HusbyS,Murray JA,KatzkaDA.AGAclinicalpracticeupdate ondiagnosisandmonitoringofCeliacdisease-changingutility ofserologyandhistologicmeasures:expertreview.Gastroen- terology.2019;156:885---9.

27.WolfJ,HaendelN,RemmlerJ,KutznerCE,KaiserT,MothesT.

HemolysisandIgA-antibodiesagainsttissuetransglutaminase:

when areantibodytestresultsnolongerreliable? JClinLab Anal.2018;32:e22360.

28.Waisbourd-ZinmanO,HojsakI,RosenbachY,Mozer-GlassbergY, ShalitinS,PhillipM,etal.Spontaneousnormalizationofanti- tissuetransglutaminaseantibodylevelsiscommoninchildren withtype1diabetesmellitus.DigDisSci.2012;57:1314---20.

29.Castellaneta S,Piccinno E,Oliva M,Cristofori F,Vendemiale M,OrtolaniF,etal.Highrateofspontaneousnormalizationof celiacserologyinacohortof446childrenwithtype1diabetes:

aprospectivestudy.DiabetesCare.2015;38:760---6.

30.Martínez-OjinagaE,MolinaM,PolancoI,UrcelayE,Nú˜nezC.

HLA-DQdistributionandriskassessmentofceliacdiseaseina Spanishcenter.RevEspEnfermDig.2018;110:421---6.

31.RomanosJ,RosénA, KumarV,TrynkaG, FrankeL, SzperlA, etal.PreventCDGroup.Improvingcoeliacdiseaseriskpredic- tionbytestingnon-HLAvariantsadditionaltoHLAvariants.Gut.

2014;63:415---22.

32.Nú˜nezC,GarroteJA,ArranzE,BilbaoJR,FernándezBa˜nares F,JiménezJ,etal.Recommendationstoreportandinterpret HLAgeneticfindingsin coeliacdisease. RevEspEnferm Dig.

2018;110:458---61.

33.Paul SP, ChopraJ,VainaCL,Mallikarjuna A, BasudeD.HLA- DQ2/DQ8typing for non-biopsydiagnosis of coeliac disease:

isitnecessary?ArchDisChild.2019;2,pii:archdischild-2019- 317297.doi:10.1136/archdischild-2019-317297.[Epubaheadof print]PubMedPMID:31375474.

34.SciurtiM,FornaroliF,GaianiF,BonaguriC,LeandroG,DiMario F,etal.Geneticsusceptibiltyandceliacdisease:whatroledo HLAhaplotypesplay?ActaBiomed.2018;89(9-S):17---21.

35.AndersonRP,HenryMJ,TaylorR,DuncanEL,DanoyP,CostaMJ, etal.Anovelserogeneticapproachdeterminesthecommunity prevalenceofceliacdiseaseandinformsimproveddiagnostic pathways.BMCMed.2013;11:188.

36.TaavelaJ,KoskinenO,HuhtalaH,LähdeahoML,PoppA,Laurika K,etal.Validationofmorphometricanalysesofsmall-intestinal biopsyreadoutsinceliacdisease.PLoSOne.2013;1:8.

37.OberhüberG,GranditschG,Vogelsang H.Thehistopathology ofceliacdisease:timefor astandardizedreportscheme for pathologists.EurJGastroenterolHepatol.1999;11:1185---94.

38.RostamiK,AldulaimiD,HolmesG,JohnsonMW,RobertM,Sri- vastava A, etal. Microscopicenteritis: Bucharestconsensus.

WorldJGastroenterol.2015;21:2593---604.

39.AuricchioR,ToscoA,PiccoloE,GalatolaM,IzzoV,MaglioM, etal.Potentialceliacchildren:9-yearfollow-uponagluten- containingdiet.AmJGastroenterol.2014;109:913---21.

40.Benelli E, Carrato V, Martelossi S, Ronfani L, Not T, Ven- tura A.Coeliac diseaseintheERA ofthenewESPGHAN and BSPGHANguidelines:aprospectivecohortstudy.ArchDisChild.

2016;101:172---6.

41.LernerBA, GreenPHR, LebwohlB. Going againstthegrains:

gluten-freedietsinpatientswithoutceliacdisease-worthwhile ornot?DigDisSci.2019;64:1740---7.

Referencias

Documento similar

“ CLIL describes a pedagogic approach in which language and subject area content are learnt in combination, where the language is used as a tool to develop new learning from a

The general idea of the language is to “thread together,” so to speak, existing systems that parse and analyze single web pages into a navigation procedure spanning several pages of

No obstante, como esta enfermedad afecta a cada persona de manera diferente, no todas las opciones de cuidado y tratamiento pueden ser apropiadas para cada individuo.. La forma

It is generally believed the recitation of the seven or the ten reciters of the first, second and third century of Islam are valid and the Muslims are allowed to adopt either of

In the preparation of this report, the Venice Commission has relied on the comments of its rapporteurs; its recently adopted Report on Respect for Democracy, Human Rights and the Rule

The main goal of this thesis is to contribute to the knowledge in planetary science through the study of the upper atmosphere of giant planets undergoing hydrody- namic escape. We

† Joint position statement of the European Academy of Paediatric (EAP), the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), the European

teriza por dos factores, que vienen a determinar la especial responsabilidad que incumbe al Tribunal de Justicia en esta materia: de un lado, la inexistencia, en el