Clinical and pathological spectrum of coeliac disease--active, silent, latent, potential.

Gu 1993; 34: 150-151 Leading a icle Clinical and pa hological spec um o coeliac disease - ac i e, silen , la en , po en ial Cu en ly ecognised o ms o glu en sensi i e en e opa hy Wi hin he amewo k o he cu en de ini ion (a pe manen glu en sensi i e en e opa hy), clinical, pa hological, epidemiological, and immunological app oaches a e e eal- ing se e al o ms o coeliac disease. In so called ac i e coeliac disease, malabso p ion, and nu i ional de iciencies ange om p o ound o minimal; clinically silen coeliac disease is being inc easingly ecognised - o example, in amily s udies. Pa hologically he e is also a deg ee o he e ogenei y. Desc ip i e e ms such as ' la mucosa', o 'sub o al illus a ophy', a e he pa hologis 's sho hand o a clus e o ea u es ( illus, c yp sizes, epi helial cell damage, in a- epi helial and lamina p op ia lymphoid cell in il a es) which oge he cha ac e ise he en e opa hy o coeliac disease. Quan i a i e his ology and compu e ised image analysis ha e shown ha hese ea u es occu in a con inuum, wi h he la lesion a one end o he spec um and a mucosa wi h no mal illus and c yp a chi ec u e, bu an abno mally high densi y o coun o illus in aepi helial lymphocy es, a he o he . 2 The la e would be epo ed as no mal by mos clinical pa hologis s. This ac is impo an when he e idence o he exis ence o la en coeliac disease is e iewed. This e m should only be applied o pa ien s who ul il he ollowing condi ions: (i) ha e a no mal jejunal biopsy while aking a no mal die ; (ii) a some o he ime, be o e o since, ha e had a la jejunal biopsy which eco e s on a glu en ee die . The sugges ion ha he e migh be a 'p ecoeliac' s a e was i s made by Weins ein who desc ibed wo pa ien s wi h de ma i is he pe i o mis and no mal jejunal biopsies in whom ypical coeliac like en e opa hy de eloped some weeks a e 20 g glu en was added o hei al eady glu en con ain- ing die .3 Two s udies om he Uni ed Kingdom ha e con- i med his obse a ion45 and he concep is suppo ed by case epo s o coeliac pa ien s in whom, by chance, a jejunal biopsy has p e iously been aken and epo ed as no mal."8 Sub le pa hological and immunological abno mali ies in some la en coeliacs I ull mo phome ic analysis we e o show changes a he mild end o he spec um o coeliac like en e opa hy in he o iginal biopsies (as has been epo ed in wo such pa ien s)8 his would equi e ha he desc ip i e e m in hese cases be e ised om la en o low g ade o mild glu en sensi i e en e opa hy. Fu he mo e, i would g ea ly acili a e esea ch and clinical managemen o such pa ien s i he e was a means o iden i ying hem, mo e widely a ailable and less echnically demanding han compu e ised image analysis. Coeliacs whose in es inal lesions ha e esol ed on a glu en ee die and whose jejunal biopsies a e classi ied as 'no mal' o diagnos ic pu poses may s ill exp ess sub le pa hological o immunological abno mali ies simila o hose o un ea ed coeliacs. These abno mali ies include a high coun o illus IEL9; inc eased gamma/del a T cell ecep o exp ession by in aepi helial lymphocy es'0; abno mal jejunal pe me- abili y"'; and high concen a ions o IgM an igliadin an ibody, o he IgM class an ibodies, and IgA an igliadin an ibody ( he 'coeliac like in es inal an ibody' pa e n) in specimens o jejunal luid and whole gu la age luid."2 One app oach o he ecogni ion o po en ial la en o low g ade coeliacs is by s udies o in aepi helial lymphocy e T cells exp essing gamma/del a ecep o s. This p esen s logis ic p oblems, as he ele an immunohis ochemical s udies mus be done on ozen sec ions, bu posi i e esul s ha e been epo ed in a single case o la en coeliac disease de ec ed du ing amily s udies in Finland.7 We ecen ly epo ed ha he cha ac e is ic coeliac like in es inal an ibody pa e n o in es inal luid an ibodies also occu s in de ma i is he pe i o mis pa ien s wi hou en e o- pa hy, a g oup o pa ien s in whom i is likely ha all o mos a e in ac la en coeliacs.'3 Simila s udies o in es inal an ibodies migh acili a e he de ec ion o la en coeliac disease in o he si ua ions. Two s age model o coeliac disease We ha e p oposed a wo s age model o glu en sensi i e en e opa hy, la en and ully exp essed.'3 This de i ed om he con luence o se e al lines o clinical and expe imen al wo k and can be s a ed as ollows: induc ion o a s a e o inapp op ia e immuni y (hype sensi i i y) o gliadin is a ela i ely equen occu ence, gene ically es ic ed. The e ec s o abno mal in e ac ion be ween he immune sys em and glu en may be exp essed no only in gu (coeliac disease) and skin (de ma i is he pe i o mis), bu also in he mou h ( ecu en aph hae), kidneys (IgA neph opa hy) and join s (some a h i ides). Wi hin he in es inal mucosa, exp ession o T cell media ed immuni y o gliadin in he gu occu s ac oss a spec um o his ological and unc ional abno mali- ies. The minimal lesion may appea his ologically no mal, o as a i ually no mal biopsy wi h a high coun o illus in aepi helial lymphocy es; he ully exp essed lesion is a la mucosa wi h c yp hype plasia, ypical o coeliac disease. S udies in mice'4 showed ha immunological sensi isa ion o gliadin does no igge he de elopmen o a T cell media ed lesion o he in es ine when he die con ains glu en. Addi ional ac o s, such as hose occu ing du ing in es inal anaphylaxis o a g a - e sus-hos eac ion, we e necessa y. Enhanced an igen p esen a ion, ec ui men o speci ic T cells in he mucosa, up- egula ion o he exp ession o class II an igens and ailu e o supp ession, a e all candida e mechanisms o he e ec s obse ed. By analogy, al hough mucosal immunological sensi isa ion is an in a iable ea u e o coeliac disease, i is no he p ecipi a ing ac o o he exp ession o he ull in es inal lesion; a second ac o d i es he en e opa hy om minimal (la en ) o o e , ei he by immunological mechanisms o by di ec ancilla y e ec s on en e ocy es. Candida e ac o s include an episode o hype pe meabili y, nu ien de iciency, inc eased die a y glu en, impai ed in aluminal diges ion o inges ed glu en, adju an e ec s o in es inal in ec ion and a non-HLA associa ed gene. Signi icance o a high coun o in aepi helial lymphocy es In animal wo k on delayed ype hype sensi i i y in oden 150 on Augus 23, 2020 by gues . P o ec ed by copy igh .h p://gu .bmj.com/Gu : i s published as 10.1136/gu .34.2.150 on 1 Feb ua y 1993. Downloaded om Clinical and pa hological spec um o coeliac disease - ac i e, silen , la en , po en ial 151 in es ine, a ise in he coun o illus in aepi helial lympho- cy es was a sensi i e and ea ly ea u e o he exp ession o mucosal delayed ype hype sensi i i y'5 and is induced by signals om ac i a ed lamina p op ia CD4 T cells.'6 By analogy, in clinical p ac ice a high coun o in aepi helial lymphocy es in an a chi ec u ally no mal small bowel biopsy will also imply a s a e o T cell ac i a ion, ei he an igen d i en - o example, by glu en, gia dia, his ocompa ibili y an igens - o as a esul o abe an mucosal immuno egula- ion (as in some heo ies o he pa hogenesis o in lamma o y bowel disease). The e is now a subs an ial body o e idence ha he exp ession o glu en hype sensi i i y as en e opa hy may be minimal, measu able only i a coun o in aepi helial lymphocy es is pe o med. An accep ed name o his ype o pa hology is needed, such as 'high densi y in aepi helial lymphocy e en e opa hy'. This mus be clea ly di e en ia ed om a ious o he o ms o non-coeliac en e opa hy, such as ha o HIV in ec ion.'7 Fu he wo k will show how a high coun o in aepi helial lymphocy es ela es o gamma del a in aepi helial lymphocy e coun s, and whe he hese a e me ely sensi i e indices o mucosal delayed ype hype - sensi i i y exp ession, and all associa ed wi h p oduc ion o IL2 and gamma in e e on, o whe he high densi y o in aepi helial lymphocy es, he unusual up egula ion o IgM and/o gamma del a T cell numbe s a e independen ac o s, pe haps gene ically de e mined, ele an o he induc ion o a s a e o abe an immuni y o glu en, and hus di ec ly o he pa hogenesis o coeliac disease. Clinical impo ance o an ex ension o he pa hological c i e ia o coeliac disease We ha e ecen ly assessed he equency o he coeliac like in es inal an ibody pa e n, a candida e ma ke o la en coeliac disease, in pa ien s e e ed o diagnos ic small bowel biopsy. S udies o jejunal luid e ealed he coeliac like in es inal an ibody pa e n in 16 o 98 non-coeliac cases, o whom six also had a high coun o in aepi helial lymphocy es (A anz and Fe guson, submi ed). I u he esea ch shows ha some o hese pa ien s a e clinically glu en sensi i e (and we al eady ha e some e idence o suppo his), hen by implica ion, he p e ious de ini ion o coeliac disease (a la mucosa) may ha e excluded up o hal o symp oma ic pa ien s, e e ed o jejunal biopsy, who would bene i clinically om a glu en ee die . The p esen pa hological desc ip ion o coeliac disease may need o be e ised and ea men wi h a glu en ee die (ca e ully moni o ed) o e ed o symp oma ic pa ien s wi h mino o ms o en e opa hy. Only a ely, and usually by chance - o example, p e ious biopsy in a esea ch in es iga ion - does a pa ien ul il c i e ia o la en coeliac disease. A mo e gene ally applicable exp ession is needed o desc ibe people who should ha e he diagnosis o la en o low g ade coeliac disease conside ed - such as hose wi h high in aepi helial lymphocy e coun , posi i e coeliac like in es inal an ibody pa e n, high gamma del a exp ession o in aepi helial lymphocy es, ela i es o coeliacs, IgA de icien indi iduals. The e m 'po en ial coeliac disease' is p oposed.8 A FERGUSON E ARRANZ S O'MAHONY Gas oin es inal Uni , Wes e n Gene al Hospi al and Uni e si y o Edinbu gh, Edinbu gh EH4 2XU 1 Ziegle K, Fe guson A. Coeliac disease. In: Ba RM, Law ence TLJ, eds. Func ion and dys unc ion o he small in es ine. Li e pool: Li e pool Uni e si y P ess, 1984: 149-66. 2 Ma sh MN. S udies o in es inal lymphoid issue. XI. The immunopa hology o cell-media ed eac ions in glu en sensi i i y and o he en e opa hies. ScanningMic osc 1988; 2: 1663-84. 3 Weins ein WM. La en celiac sp ue. Gas oen e ology 1974; 66: 489-93. 4 Dohe y M, Ba y RE. Glu en induced mucosal changes in subjec s wi hou o e small-bowel disease. Lance 1981; i: 517-20. 5 Fe guson A, Blackwell JN, Ba neson RS C. E ec s o addi ional die a y glu en on he small-in es inal mucosa o olun ee s and o pa ien s wi h de ma i is he pe i o mis. ScandJ Gas oen e ol 1987; 22: 543-9. 6 Maki M, Holm K, Koskimies S, Halls om 0, Visako pi JK. No mal small bowel biopsy ollowed by coeliac disease. A ch Dis Child 1990; 65: 1137-41. 7 Maki M, Holm K, Collin P, Sa ilah i E. Inc ease in T/6 T cell ecep o bea ing lymphocy es in no mal small bowel mucosa in la en coeliac disease. Gu 1991; 32: 1412-4. 8 Ma sh MN. S udies o in es inal lymphoid issue. XIII. Immunopa hology o he e ol ing celiac sp ue lesion. Pa hol Res P ac 1989; 185: 774-7. 9 Fe guson A, Mu ay D. Quan i a ion o in aepi helial lymphocy es in human jejunum. Gu 1971; 12: 988-94. 10 Sa ilah i E, A a o A, Ve kasalo M. In es inal T/b ecep o -bea ing T lymphocy es in celiac disease and in lamma o y diseases in child en. Cons an inc ease in celiac disease. Pedia Res 1990; 28: 579-81. 11 Bja nason I, Pe e s TJ, Veall N. A pe sis en de ec in in es inal pe meabili y in coeliac disease demons a ed by a 51C - labelled EDTA abso p ion es . Lance 1983; i: 323-5. 12 O'Mahony S, A anz E, Ba on JR, Fe guson A. Dissocia ion be ween sys emic and mucosal immune esponses in coeliac disease. Gu 1991; 32: 29-35. 13 O'Mahony S, Ves ey JP, Fe guson A. Simila i ies in in es inal humo al immuni y in de ma i is he pe i o mis wi hou en e opa hy and in coeliac disease. Lance 1990; 335: 1487-90. 14 T oncone R, Fe guson A. An animal model o glu en-induced en e opa hy in mice. Gu 1991; 32: 871-5. 15 Fe guson A. Models o immunologically-d i en small in es inal damage. In: Ma sh MN, ed. Immunopa hology o he small in es ine. Chiches e : John Wiley, 1987: 225-52. 16 Mowa AM, Bo land A, Pa o DMV. The in es inal phase o immune g a - e sus-hos eac ion is induced by Ly2 T cells ac i a ed by I-A alloan igens. T ansplan a ion 1986; 41: 192-8. 17 Anonymous. HIV-associa ed en e opa hy [Edi o ial]. Lance 1989; ii: 777-8. 18 Fe guson A, A anz E, O'Mahony S. De ini ions and diagnos ic c i e ia o la en and po en ial coeliac disease. In: Common ood in ole ances 1: Epidemi- ology o coeliac disease. Ed: Au icchio S, Visako pi JK. Basle: Ka ge , 1992 (in p ess). on Augus 23, 2020 by gues . P o ec ed by copy igh .h p://gu .bmj.com/Gu : i s published as 10.1136/gu .34.2.150 on 1 Feb ua y 1993. Downloaded om