nu ien s
Re iew
Glu en-Induced Ex a-In es inal Mani es a ions in
Po en ial Celiac Disease—Celiac T ai
Alina Popp 1,2 and Ma kku Mäki 2,*
1Uni e si y o Medicine and Pha macy “Ca ol Da ila” and Na ional Ins i u e o Mo he and Child Heal h
“Alessand escu-Rusescu”, Bucha es 020395, Romania; [email p o ec ed]
2Facul y o Medicine and Heal h Technology, Tampe e Uni e si y and Tampe e Uni e si y Hospi al,
33520 Tampe e, Finland
*Co espondence: [email p o ec ed]; Tel.: +358-50-3656668
Recei ed: 21 Decembe 2018; Accep ed: 29 Janua y 2019; Published: 1 Feb ua y 2019


Abs ac :
Celiac disease pa ien s may su e om a numbe o ex a-in es inal diseases ela ed o
long- e m glu en inges ion. The diagnosis o celiac disease is based on he p esence o a mani es
small in es inal mucosal lesion. Indi iduals wi h a no mal biopsy bu an inc eased isk o de eloping
celiac disease a e e e ed o as po en ial celiac disease pa ien s. Howe e , hese pa ien s a e no
ea ed. This e iew highligh s ha pa ien s wi h no mal biopsies may su e om he same
ex a-in es inal glu en-induced complica ions be o e he disease mani es s a he in es inal le el.
We discuss diagnos ic ma ke s e ealing ue po en ial celiac disease. The e idence-based medical
li e a u e shows ha hese po en ial pa ien s, who a e “excluded” o celiac disease would in ac
bene i om glu en- ee die s. The ques ion is why wai o an end-s age disease o occu when
i can be p e en ed? We u ilize esea ch on de ma i is he pe i o mis, which is a model disease
in which a glu en-induced en i y e up s in he skin i espec i e o he s a e o he small in es inal
mucosal mo phology. Fu he mo e, glu en a axia can be ca ego ized as i s own en i y. The o he
ex a-in es inal mani es a ions occu ing in celiac disease a e also ound a he la en disease s age.
Consequen ly, pa ien s wi h celiac ai s should be iden i ied and ea ed.
Keywo ds:
glu en; la en celiac disease; po en ial celiac disease; ex a-in es inal mani es a ions; mild
en e opa hy; ea ly de eloping celiac disease; gene ic glu en in ole ance; na u al his o y; celiac ai
1. In oduc ion
Celiac disease is an au oimmune sys emic diso de in gene ically suscep ible pe sons pe pe ua ed
by he daily inges ion o glu en ce eals (whea , ye, and ba ley) wi h mani es a ions in he small
in es ine and o gans ou side he gu . Pa ien s diagnosed wi h celiac disease show glu en-induced and
glu en-dependen duodenal mucosal lesions (i.e., he ypical c yp hype plas ic lesion wi h illous
a ophy). Clinically hese newly diagnosed pa ien s may o may no be su e ing om gas oin es inal
symp oms. A glu en-d i en ex a-in es inal mani es a ion is o en he only clue o he disease. In he
p ima y ca e and wi hin di e en medical disciplines, physicians should suspec celiac disease and
pe o m case inding by se um au oan ibody sc eening. Posi i e se ology is o en he only way o
iden i y po en ial pa ien s o a diagnos ic uppe in es inal endoscopy [
1
–
3
]. In ac , less han hal o
all adul pa ien s diagnosed wi h celiac disease complain o gas oin es inal symp oms a an ini ial
diagnosis [
4
]. This knowledge comes om Finland, whe e adul celiac disease diagnoses ha e inc eased
20 imes in ecen decades and 0.8% o he o al popula ion has a biopsy-con i med diagnosis [5–7].
Pa ien s diagnosed wi h celiac disease including a duodenal mucosal lesion may su e om
a numbe o ex a-in es inal diseases [
2
,
3
]. De ma i is he pe i o mis mani es s ou side he gu , is
glu en d i en and dependen [
8
,
9
], has he same gene ic backg ound, and occu s wi hin he same
Nu ien s 2019,11, 320; doi:10.3390/nu11020320 www.mdpi.com/jou nal/nu ien s
Nu ien s 2019,11, 320 2 o 12
amilies as celiac disease [
9
,
10
]. In ac , one iden ical win may ha e celiac disease while he o he
su e s om de ma i is he pe i o mis [
11
]. O he glu en-d i en ex a-in es inal mani es a ions in celiac
disease include os eopenia, os eopo osis, ac u es [
12
–
14
], pe manen oo h enamel de ec s [
6
,
15
],
a h i is, and a h algia [
16
–
18
] as well as u he cen al and pe iphe al ne ous sys em [
19
–
22
],
li e [
23
–
25
], and ep oduc i e sys em in ol emen s [
26
,
27
]. E en au oimmune diseases may be glu en
d i en [
28
,
29
], and he e is a isk o malignan complica ions, especially non-Hodgkin lymphoma, in
un ea ed celiac disease [30,31].
By de ini ion, celiac disease is excluded in pa ien s who ha e no mal small in es inal mucosal
mo phology a hei i s diagnos ic endoscopy i hey ha e been ollowing a no mal glu en-con aining
die . Howe e , i seems e iden ha his is no accu a e. In a e iew in 2001, we w o e ha
glu en-induced ex a-in es inal mani es a ions may de elop a he la en disease s age when he
mucosa is s ill mo phologically no mal [
32
], ci ing se e al obse a ions [
19
,
33
–
36
]. Today such pa ien s
a e o en e e ed o as ha ing “po en ial celiac disease” because hey a e ound o be “no mal” on
biopsy [
37
]. Meanwhile, de ma i is he pe i o mis is ou model disease, in which an ex a-in es inal
mani es a ion is ea ed wi h a glu en- ee die i espec i e o he mucosal inding (diseased o no ).
We e iewed he li e a u e o e idence o ex a-in es inal glu en-dependen mani es a ions in pa ien s
“excluded” o celiac disease. In his pape , we also discuss ools o iden i ying hese “po en ial”
ea able pa ien s.
2. La en o Po en ial Celiac Disease
The “p e-celiac” s a e has been desc ibed in pa ien s wi h de ma i is he pe i o mis, in whom
small in es inal mucosal de e io a ion was shown o occu a e adding ex a glu en o he die [
38
–
40
].
An ex a glu en load also induced mucosal lesions in heal hy indi iduals [
39
,
41
]. The concep o la en
celiac disease, wi hou ha ing an ex a load o glu en, was shown o be pa o he glu en sensi i i y
spec um and na u al his o y o celiac disease [
42
–
45
]. Speci ically, his was shown in Finland in celiac
pa ien s who, by chance, had p e iously unde gone a small in es inal biopsy ha was epo ed as
no mal o who we e ollowed up because o posi i e se um au oan ibody esul s.
We chose o use he e m “la en celiac disease”, which is simila o Weins ein [
38
], when e e ing
o pa ien s wi h a no mal biopsy who la e exhibi ed mucosal de e io a ion and we e diagnosed as
celiac disease pa ien s. Fo us, “la en ” means exis ing bu no mani es (i.e., he disease exis s bu is
no mani es a he mucosal le el). Based on ou ea ly desc ip ions, Fe guson e al. (1993) de ined
la en celiac disease as ollows: “This e m should only be applied o pa ien s who ul ill 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 ” [
46
]. Following he i s
epo s on exis ing celiac disease la ency, a numbe s o o he esul s ha e been published, wi h ea ly
pape s by T oncone [
47
] and Co azza e al. [
48
]. I is now clea ha o al ole ance owa ds glu en can
be kep o longe pe iods, e en o decades and in o olde age [49].
The e m “po en ial celiac disease” has been used in e changeably wi h la en celiac disease,
and his has led o con usion in he celiac disease li e a u e. Thus, he Oslo ask o ce discou aged he
use o he e m “la en celiac disease”, and indi iduals wi h a no mal ou come om a small in es inal
biopsy bu who a e a inc eased isk o de eloping celiac disease based on posi i e celiac disease
se ology should be e e ed o as ha ing po en ial celiac disease [
37
]. These “po en ial pa ien s” a e
no ea ed as celiac. The ques ion is, wha should a glu en- igge ed and glu en-dependen ea able
disease ou side he gu be called, when he ex a-in es inal mani es a ion occu s a he la en s age o
he disease and when con en ional diagnos ic biopsy c i e ia ha e excluded celiac disease? We in e
ha such pa ien s should no be ca ego ized as ha ing po en ial celiac disease. Ra he , hey equi e
p ope ea men [50,51].
In Figu e 1, we summa ize he li espan na u al his o y o celiac glu en sensi i i y, whe e each
line ep esen s a single indi idual. The e m celiac glu en sensi i i y encompasses celiac ai s, la en
celiac disease, gene ic glu en in ole ance, mild en e opa hy celiac disease, ea ly de eloping celiac
Nu ien s 2019,11, 320 3 o 12
disease, and celiac disease i sel [
1
,
32
,
50
–
53
]. The glu en-induced mucosal damage de elops apidly
o g adually om no mal mucosal mo phology o a mani es mucosal lesion. The ole ance owa ds
glu en is indi idual, and i may be b oken a e only mon hs o yea s (childhood celiac disease) bu
also a adolescence, adul hood, and e en a e decades o glu en inges ion in old age. The la en celiac
disease pa ien s, he “ ue po en ial” pa ien s in Figu e 1(i.e., no mal on biopsy showing illus heigh
c yp dep h a io >2), a e classi ied as ha ing celiac disease only when he disease has de e io a ed o
he deg ee o a mani es mucosal lesion (i.e., illus heigh c yp dep h a io <2).
Nu ien s 2018, 10, x FOR PEER REVIEW 3 o 12
o g adually om no mal mucosal mo phology o a mani es mucosal lesion. The ole ance owa ds
glu en is indi idual, and i may be b oken a e only mon hs o yea s (childhood celiac disease) bu
also a adolescence, adul hood, and e en a e decades o glu en inges ion in old age. The la en celiac
disease pa ien s, he “ ue po en ial” pa ien s in Figu e 1 (i.e., no mal on biopsy showing illus heigh
c yp dep h a io >2), a e classi ied as ha ing celiac disease only when he disease has de e io a ed o
he deg ee o a mani es mucosal lesion (i.e., illus heigh c yp dep h a io <2).
Figu e 1. Na u al his o y o de eloping celiac disease (CD) a he small in es inal mucosal le el. Each
line ep esen s one indi idual. We a e bo n wi h a no mal mucosal mo phology, a illus heigh (VH),
and a c yp dep h (C D) a io o app oxima ely h ee and illi h ee imes alle han c yp s a e deep.
Upon glu en inges ion, mucosal inju y p oceeds apidly o g adually a di e en ages, in childhood
o only a an olde age. Be o e de eloping a mani es mucosal lesion (diseased mucosa on biopsy,
VH:C D <2) e e y CD pa ien belongs o he ca ego y la en “ ue po en ial” CD (no mal on biopsy,
VH:C D >2).
3. Ma ke s o Exis ing Ea ly Disease
An exis ing glu en-dependen disease wi hou e idence o en e opa hy un il a la e age - la en
celiac disease - includes in i s de ini ion he suscep ibili y genes o celiac disease and he genes
encoding he human leukocy e an igen (HLA) DQ2 o DQ8 molecules [1,32,54]. This is a check ha
clinicians may pe o m when he e a e symp oms and signs sugges i e o celiac disease, bu he
biopsy is no mal o does no show clea c yp hype plasia. I shows only in lamma ion and
desc ip i e mild illus a ophy. Posi i i y o DQ2 o DQ8 does no mean e y much, since 30% o
40% o he ci izens in he coun y a e posi i e, bu double nega i e means ha no celiac disease will
de elop.
Pa ien s posi i e o celiac disease se ology wi h no mal biopsies should be conside ed o ha e
po en ial celiac disease [37]. Howe e , gliadin an ibody posi i i y, which is a equen inding in
celiac disease con ol pa ien s and e en in heal hy indi iduals, does no co ela e wi h celiac disease
suscep ibili y genes [55]. Cu en ly, issue ansglu aminase au oan ibody (TG2-ab) es ing is used o
sc een o celiac disease. I should be no ed, howe e , ha no all se um TG2-abs p edic celiac disease
[56]. TG2-abs ha e been desc ibed in o he au oimmune diseases as well as in in ec ions, umo s,
myoca dial damage, li e diso de s, and pso iasis [54]. These an ibodies a e no associa ed wi h
endomysial au oan ibodies and may occu in pe sons nega i e bo h o HLA DQ2 and DQ8. The
se um endomysial an ibody es is he gold s anda d, and he p esence o hese au oan ibodies
Figu e 1.
Na u al his o y o de eloping celiac disease (CD) a he small in es inal mucosal le el. Each
line ep esen s one indi idual. We a e bo n wi h a no mal mucosal mo phology, a illus heigh (VH),
and a c yp dep h (C D) a io o app oxima ely h ee and illi h ee imes alle han c yp s a e deep.
Upon glu en inges ion, mucosal inju y p oceeds apidly o g adually a di e en ages, in childhood o
only a an olde age. Be o e de eloping a mani es mucosal lesion (diseased mucosa on biopsy, VH:C D
<2) e e y CD pa ien belongs o he ca ego y la en “ ue po en ial” CD (no mal on biopsy, VH:C D >2).
3. Ma ke s o Exis ing Ea ly Disease
An exis ing glu en-dependen disease wi hou e idence o en e opa hy un il a la e age - la en
celiac disease - includes in i s de ini ion he suscep ibili y genes o celiac disease and he genes
encoding he
human leukocy e an igen
(HLA) DQ2 o DQ8 molecules [
1
,
32
,
54
]. This is a check ha
clinicians may pe o m when he e a e symp oms and signs sugges i e o celiac disease, bu he biopsy
is no mal o does no show clea c yp hype plasia. I shows only in lamma ion and desc ip i e mild
illus a ophy. Posi i i y o DQ2 o DQ8 does no mean e y much, since 30% o 40% o he ci izens
in he coun y a e posi i e, bu double nega i e means ha no celiac disease will de elop.
Pa ien s posi i e o
celiac disease se ology
wi h no mal biopsies should be conside ed o ha e
po en ial celiac disease [
37
]. Howe e , gliadin an ibody posi i i y, which is a equen inding
in celiac disease con ol pa ien s and e en in heal hy indi iduals, does no co ela e wi h celiac
disease suscep ibili y genes [
55
]. Cu en ly, issue ansglu aminase au oan ibody (TG2-ab) es ing
is used o sc een o celiac disease. I should be no ed, howe e , ha no all se um TG2-abs
p edic celiac disease [
56
]. TG2-abs ha e been desc ibed in o he au oimmune diseases as well
as in in ec ions, umo s, myoca dial damage, li e diso de s, and pso iasis [
54
]. These an ibodies
a e no associa ed wi h endomysial au oan ibodies and may occu in pe sons nega i e bo h o HLA
DQ2 and DQ8. The se um endomysial an ibody es is he gold s anda d, and he p esence o hese
Nu ien s 2019,11, 320 4 o 12
au oan ibodies p edic s impending celiac disease [
1
,
45
,
50
,
53
,
55
]. In celiac disease in pa ien s wi h
ex a-in es inal mani es a ions, o he au oan ibodies play a ole in diagnosis and po en ially in disease
mechanisms [57].
A he mucosal le el, in lamma ion, as measu ed as he densi y o in aepi helial T cells
(
IELs
), is a e y unspeci ic inding, bu is also glu en-dependen in cases o celiac disease [
58
].
Ma sh 1 lesions wi h inc eased IELs we e shown o ha e a sensi i i y o 59% and speci ici y o
57% in p edic ing o hcoming celiac disease [
59
]. Howe e , when sea ched o , an au oimmune
insul o he mo phologically no mal in es inal mucosa is, in ac , p esen . A high densi y o
γδ
T-cell- ecep o -bea ing IELs
in pa ien s wi h mo phologically no mal mucosa who also ca y he
suscep ibili y genes o celiac disease seems o be a p e equisi e o de eloping celiac disease [
43
,
60
,
61
].
Ye , e en i an inc eased densi y o
γδ
T cells is ound in la en celiac disease, such a inding is no
pa hognomonic o he disease [
59
,
61
]. In he small in es ine, he glu en-dependen au oan ibodies
a ge ex acellula TG2 and may be de ec ed as
IgA deposi s
in biopsy issues a he la en disease
s age [
62
–
64
] (Figu e 2). In ac , he IgA deposi s in he duodenal biopsies accu a ely p edic ed
o hcoming celiac disease be e han IELs,
γδ+
IELs, o se um au oan ibodies [
59
]. The de ec ion
o in es inal TG2-abs by phage-an ibody lib a ies is ano he possibili y o diagnosis [
52
]. Howe e ,
in es inal TG2-ab p oduc ion is no only ound in celiac disease [
65
]. Again, when inding an inc eased
densi y o
γδ+
IELs o IgA deposi s in a pa ien wi h no mal small in es inal mucosal mo phology, i is
ecommended o check whe he he pa ien belongs o he “celiac amily” (i.e., a e ca ying ei he he
HLA DQ2 o DQ8 molecules).
Nu ien s 2018, 10, x FOR PEER REVIEW 4 o 12
p edic s impending celiac disease [1,45,50,53,55]. In celiac disease in pa ien s wi h ex a-in es inal
mani es a ions, o he au oan ibodies play a ole in diagnosis and po en ially in disease mechanisms
[57].
A he mucosal le el, in lamma ion, as measu ed as he densi y o in aepi helial T cells (IELs),
is a e y unspeci ic inding, bu is also glu en-dependen in cases o celiac disease [58]. Ma sh 1
lesions wi h inc eased IELs we e shown o ha e a sensi i i y o 59% and speci ici y o 57% in
p edic ing o hcoming celiac disease [59]. Howe e , when sea ched o , an au oimmune insul o he
mo phologically no mal in es inal mucosa is, in ac , p esen . A high densi y o γδ T-cell- ecep o -
bea ing IELs in pa ien s wi h mo phologically no mal mucosa who also ca y he suscep ibili y genes
o celiac disease seems o be a p e equisi e o de eloping celiac disease [43,60,61]. Ye , e en i an
inc eased densi y o γδ T cells is ound in la en celiac disease, such a inding is no pa hognomonic
o he disease [59,61]. In he small in es ine, he glu en-dependen au oan ibodies a ge ex acellula
TG2 and may be de ec ed as IgA deposi s in biopsy issues a he la en disease s age [62–64] (Figu e
2). In ac , he IgA deposi s in he duodenal biopsies accu a ely p edic ed o hcoming celiac disease
be e han IELs, γδ+ IELs, o se um au oan ibodies [59]. The de ec ion o in es inal TG2-abs by phage-
an ibody lib a ies is ano he possibili y o diagnosis [52]. Howe e , in es inal TG2-ab p oduc ion is
no only ound in celiac disease [65]. Again, when inding an inc eased densi y o γδ+ IELs o IgA
deposi s in a pa ien wi h no mal small in es inal mucosal mo phology, i is ecommended o check
whe he he pa ien belongs o he “celiac amily” (i.e., a e ca ying ei he he HLA DQ2 o DQ8
molecules).
Figu e 2. Small in es inal mucosal immunoglobulin (Ig) A deposi s a e shown in a illus ip om a
de ma i is he pe i o mis pa ien wi h no mal mucosal mo phology. IgA is s ained wi h g een (A),
ansglu aminase 2 (TG2) wi h ed (B), and subepi helial colocalisa ion o IgA and TG2 can be seen in
yellow (C).
4. Ex ain es inal Mani es a ions
4.1. De ma i is He pe i o mis
In de ma i is he pe i o mis, a glu en-induced and glu en-dependen mani es a ion occu s
ou side he gu e en in he absence o in es inal mucosal illous a ophy [8,66]. Today, up o 30% o
pa ien s wi h de ma i is he pe i o mis ha e a no mal small in es inal mucosal lining [67]. Typically,
he disease mani es s wi h i chy papules and esicles on he elbows, knees and bu ocks, and o e
gas oin es inal symp oms a e a e [67,68]. When pa ien s wi hou en e opa hy a e challenged wi h
ex a glu en, hei small in es inal mucosae de e io a e in a way ypical o celiac disease [38–40].
When no en e opa hy is p esen , pa ien s only es posi i ely o se um TG2-abs and endomysial
an ibodies in 40% o cases [67]. Howe e , he pa ien s could be se um endomysial au oan ibody
posi i e al eady while ha ing no mal small in es inal mucosa p io o any e idence o skin e up ions
[44]. I sea ched o , he au oimmune e ec o he mo phologically no mal in es inal mucosa caused
by an en i onmen al igge — he daily inges ion o glu en—is, in ac , p esen . Mucosal
in lamma o y ma ke s (i.e., he high densi y o γδ+ IELs) shows his [35]. Fu he mo e, in pa ien s
Figu e 2.
Small in es inal mucosal immunoglobulin (Ig) A deposi s a e shown in a illus ip om
a de ma i is he pe i o mis pa ien wi h no mal mucosal mo phology. IgA is s ained wi h g een (
A
),
ansglu aminase 2 (TG2) wi h ed (
B
), and subepi helial colocalisa ion o IgA and TG2 can be seen in
yellow (C).
4. Ex ain es inal Mani es a ions
4.1. De ma i is He pe i o mis
In de ma i is he pe i o mis, a glu en-induced and glu en-dependen mani es a ion occu s ou side
he gu e en in he absence o in es inal mucosal illous a ophy [
8
,
66
]. Today, up o 30% o pa ien s
wi h de ma i is he pe i o mis ha e a no mal small in es inal mucosal lining [
67
]. Typically, he disease
mani es s wi h i chy papules and esicles on he elbows, knees and bu ocks, and o e gas oin es inal
symp oms a e a e [
67
,
68
]. When pa ien s wi hou en e opa hy a e challenged wi h ex a glu en, hei
small in es inal mucosae de e io a e in a way ypical o celiac disease [
38
–
40
]. When no en e opa hy is
p esen , pa ien s only es posi i ely o se um TG2-abs and endomysial an ibodies in 40% o cases [
67
].
Howe e , he pa ien s could be se um endomysial au oan ibody posi i e al eady while ha ing no mal
small in es inal mucosa p io o any e idence o skin e up ions [
44
]. I sea ched o , he au oimmune
e ec o he mo phologically no mal in es inal mucosa caused by an en i onmen al igge — he daily
inges ion o glu en—is, in ac , p esen . Mucosal in lamma o y ma ke s (i.e., he high densi y o
Nu ien s 2019,11, 320 5 o 12
γδ+
IELs) shows his [
35
]. Fu he mo e, in pa ien s who a e nega i e o se um au oan ibodies, he
an ibodies a e ound a he mucosal le el a ge ing ex acellula TG2 [
62
,
69
,
70
], which is a inding
ypical o an exis ing disease ha is no mani es a he mucosal a chi ec u al le el (Figu e 2).
We in e ha pa ien s wi h glu en- igge ed ex a-in es inal mani es a ions, who a e now classi ied
as ha ing de ma i is he pe i o mis bu show a no mal small in es inal mucosa, do no belong o he
ca ego y o po en ial celiac disease. These pa ien s may e en be su e ing om os eopo osis and
expe ience bone ac u es. Clea ly, i is a ea able disease [
67
,
68
,
71
]. In he ollowing, we use pa allel
easoning o pa ien s ha ing o he glu en-dependen ex a-in es inal mani es a ions occu ing a he
la en s age o celiac disease.
4.2. Cen al and Pe iphe al Ne ous Sys em
Glu en-induced neu ological mani es a ions including glu en a axia a e common in adul celiac
disease [
19
–
22
] and occu in child en [
2
]. Hadji assiliou e al. no iced ha glu en sensi i i y was ound
in pa ien s wi h neu ological disease, and hey sc eened he pa ien s wi h gliadin an ibodies [
72
]. They
also showed ha neu ological complica ions occu ed du ing he la en s age o celiac disease. Thei use
o gliadin an ibodies c ea ed some skep icism owa d he indings, bu oday glu en a axia has become
a glu en-induced en i y in i sel , simila o de ma i is he pe i o mis [
20
,
73
]. In ac , i was shown ha
glu en a axia migh espond o a s ic glu en- ee die e en in he absence o an en e opa hy [
74
,
75
].
Se um ansglu aminase 6 an ibodies a e used o de ec ing glu en a axia in pa ien s wi h and wi hou
small in es inal mucosal lesions. Nega i e se ocon e sion esul s om a glu en- ee die [
75
]. Fu he
e idence ha glu en a axia wi hou en e opa hy belongs o he celiac spec um comes om he inding
ha TG2-speci ic au oan ibody deposi s we e de ec ed in he in es inal mucosa [
74
]. The pa ien s we e
HLA DQ2-posi i e o DQ8-posi i e. All o he con ol a axia pa ien s we e nega i e o celiac- ype HLA,
and hey had no IgA deposi s in he mucosa [
74
]. In one glu en a axia pa ien , simila TG2- a ge ed
IgA deposi s we e ound in he small essels o he b ain [
74
]. In a di e en coho o idiopa hic
a axia pa ien s, he TG2- a ge ed IgA deposi s we e again de ec ed, e en in he absence o ci cula ing
TG2-abs [76].
Glu en-induced pe iphe al ne ous sys em in ol emen o en exp esses as a symme ical
senso imo o axonal pe iphe al neu opa hy [
77
]. In pa ien s wi h o wi hou en e opa hy, neu opa hies
canno be di e en ia ed based on clinical, gene ic, o immunological g ounds [78,79].
4.3. Bone Disease
Bone diseases, os eopenia, os eopo osis, and e en ac u es a e highly p e alen in un ea ed
celiac disease [
14
,
80
,
81
]. S ic glu en- ee die s imp o e bone heal h in celiac disease and a e an
e ec i e he apy o long- e m bone mine al eco e y [13,82].
La en celiac disease pa ien s, be o e mani es ing an o e disease, migh su e om
glu en-dependen symp oms as well as os eopenia and os eopo osis [
62
,
83
–
86
]. Kaukinen e al. showed
ha eigh o 10 pa ien s wi hou illous a ophy had a bone disease, and hey all we e DQ2 posi i e [
83
].
On biopsy, i was shown ha hey belonged o he celiac spec um since hey had inc eased densi ies
o
γδ+
IELs. Fu he mo e, hei ini ial TG2 and endomysial an ibodies no malized wi h a glu en- ee
die . Dickey e al. again measu ed bone mine al densi y in 31 endomysial an ibody-posi i e pa ien s
who we e excluded o celiac disease (i.e., classi ied as ha ing Ma sh 0 o Ma sh 1 lesions). They
ound os eopenia o be p esen in 30% and os eopo osis in 10% o hese pa ien s, and he deg ee o
bone disease did no di e om ha ound in pa ien s diagnosed wi h o e celiac disease. Nega i e
se ocon e sion ollowed upon implemen a ion o a glu en- ee die in he 26 o he 27 pa ien s wi h
no mal biopsies. On he con a y, eigh pa ien s con inued hei glu en-con aining die , and se en
o hem e ol ed owa d illous a ophy compa ible wi h celiac disease wi hin one o wo yea s [
84
].
Ku ppa e al. p o ed ha he glu en- ee die had a posi i e e ec on he bone mine al densi y in
endomysial an ibody-posi i e pa ien s wi h no mal illous mo phology, which is simila o hose wi h
celiac- ype en e opa hy [
85
]. Zanini e al. concluded ha celiac disease pa ien s wi h mild en e opa hy

Nu ien s 2019,11, 320 6 o 12
ha e a ious ma ke s o exis ing malabso p ion including bone disease, and, hus, equi e ea men
wi h a glu en- ee die [86].
Pa ien s wi h ue po en ial celiac disease a e also a isk o ac u es. Pas e nack e al. showed
ha de ma i is he pe i o mis pa ien s epo ed ea lie ac u es in 45 ou o 222 cases a diagnosis.
Al oge he , 16% o he ac u es had occu ed in pa ien s wi h no mal small in es inal his ology, 35%
occu ed in pa ien s wi h pa ial illous a ophy, and 49% occu ed in pa ien s wi h sub o al illous
a ophy in Re e ence [71].
4.4. Li e Diseases
Celiac disease may ini ially p esen as a monosymp oma ic li e disease, such as c yp ogenic
hype ansaminasaemia o au oimmunue- ype o li e damage [
23
–
25
,
87
]. The e a e ew epo s o
li e inju y in po en ial o la en celiac disease. Zanini e al. obse ed ha celiac disease wi h mild
en e opa hy and posi i e celiac disease- ela ed se ology is no a mild disease. Mo eo e , hey showed
alanine amino ans e ase se um alues o be ele a ed in 9/121 (8%),
γ
-glu amyl ans e ase in 5/102
(5%), and alkaline phospha ase in 6/101 (6%) o pa ien s. The au ho s concluded ha hese pa ien s
should also be ea ed [86].
4.5. O he Ex ain es inal Mani es a ions
4.5.1. Pe manen Too h Den al Enamel De ec s
Adul pa ien s wi h celiac disease and de ma i is he pe i o mis, as well as child en wi h de ma i is
he pe i o mis, show celiac- ype den al enamel de ec s in hei pe manen den i ion [
15
,
88
–
90
]. Typical
enamel de ec s we e ound in all heal hy amily membe s o celiac disease pa ien s ound o ha e
mani es mucosal lesions. Fu he mo e, hese celiac- ype enamel de ec s occu ed wi hou small
in es inal changes and we e s ongly associa ed wi h he HLA DR3 [
34
]. Impo an ly, hese pe manen
oo h enamel de ec s a e induced by glu en inges ion in ea ly childhood, when he enamel is de eloping
(i.e., a he la en s age o celiac disease and de ma i is he pe i o mis).
4.5.2. Malignancies
In 1986, F eeman and Chiu epo ed ha in es inal lymphoma migh appea a he la en s age o
celiac disease when he mucosa is mo phologically no mal [
33
]. Howe e , i is no known whe he
un ea ed pa ien s wi hou a mani es mucosal lesion ca y an inc eased isk o malignancy. Howe e ,
he e a e many complica ions, including malignancies, ha may occu in adul hood when he pa ien
is undiagnosed by inges ing glu en. Celiac disease pa ien s diagnosed a an adul and elde ly age ha e
no had mani es mucosal lesions om ea ly childhood (Figu e 1) [42–45,48,49].
Figu e 3indica es ha all he ex a-in es inal mani es a ions induced by glu en in un ea ed celiac
disease can be de ec ed in he la en s age o he disease.
Nu ien s 2019,11, 320 7 o 12
Nu ien s 2018, 10, x FOR PEER REVIEW 7 o 12
Figu e 3. Celiac ai . Glu en-induced ex a-in es inal mani es a ions exis in bo h pa ien s wi h
no mal (la en celiac disease, CD) and diseased small in es inal mucosa (o e CD). D awing adap ed
om he “cooking po ” o splashing ex a-in es inal mani es a ions, which is i s p esen ed a he
In e na ional Celiac Disease Symposium in Dublin 1992, and om d awings in e e ences No. 34, 53,
and 54.
5. Celiac T ai
Celiac disease diagnosis equi es a glu en-induced small in es inal mucosal lesion. As indica ed
in Figu e 3, he so-called “ la ” lesion is he end s age o he mucosal inju y. Figu e 3 also summa izes
ou e iew and shows ha , when he e is a glu en-induced and glu en-dependen ex a-in es inal
mani es a ion in celiac disease, he mani es a ion can be ound in pa ien s be o e he mucosa is
diseased o when i shows only mino non-speci ic changes. Fo suscep ible pe sons, upon glu en
inges ion, celiac disease de elops g adually om no mal mucosal mo phology h ough mucosal
in lamma ion, c yp hype plasia, and illous a ophy o he “ la ” mucosal lesions [91]. When he
mucosa is mo phologically no mal and, o example, bones a e al eady ac u ing due o glu en
inges ion, we should no call his condi ion po en ial celiac disease [38]. Mo eo e , we should no
wai o he mani es mucosal lesion o de elop (i.e., celiac disease). The pa ien dese es accu a e
ea men ea ly. The bene i o ea ing hese pa ien s may be due o co ec ion o mic onu ien
de iciencies ha ing an impac on ex a-in es inal mani es a ions [58]. We sugges ha he e m celiac
ai be used in hese cases [1,32,51].
Au ho Con ibu ions: Bo h au ho s sea ched he li e a u e and con ibu ed equally in w i ing he e iew.
Funding: AP and MM we e inancially suppo ed by he Compe i i e S a e Resea ch Financing o he Expe
Responsibili y A ea o Tampe e Uni e si y Hospi al, G an No. 9V041.
Con lic s o in e es : The au ho s decla e no con lic s o in e es .
Figu e 3.
Celiac ai . Glu en-induced ex a-in es inal mani es a ions exis in bo h pa ien s wi h no mal
(la en celiac disease, CD) and diseased small in es inal mucosa (o e CD). D awing adap ed om he
“cooking po ” o splashing ex a-in es inal mani es a ions, which is i s p esen ed a he In e na ional
Celiac Disease Symposium in Dublin 1992, and om d awings in e e ences No. 34, 53, and 54.
5. Celiac T ai
Celiac disease diagnosis equi es a glu en-induced small in es inal mucosal lesion. As indica ed
in Figu e 3, he so-called “ la ” lesion is he end s age o he mucosal inju y. Figu e 3also summa izes
ou e iew and shows ha , when he e is a glu en-induced and glu en-dependen ex a-in es inal
mani es a ion in celiac disease, he mani es a ion can be ound in pa ien s be o e he mucosa is
diseased o when i shows only mino non-speci ic changes. Fo suscep ible pe sons, upon glu en
inges ion, celiac disease de elops g adually om no mal mucosal mo phology h ough mucosal
in lamma ion, c yp hype plasia, and illous a ophy o he “ la ” mucosal lesions [
91
]. When he
mucosa is mo phologically no mal and, o example, bones a e al eady ac u ing due o glu en
inges ion, we should no call his condi ion po en ial celiac disease [
38
]. Mo eo e , we should no wai
o he mani es mucosal lesion o de elop (i.e., celiac disease). The pa ien dese es accu a e ea men
ea ly. The bene i o ea ing hese pa ien s may be due o co ec ion o mic onu ien de iciencies
ha ing an impac on ex a-in es inal mani es a ions [
58
]. We sugges ha he e m celiac ai be used
in hese cases [1,32,51].
Au ho Con ibu ions: Bo h au ho s sea ched he li e a u e and con ibu ed equally in w i ing he e iew.
Funding:
A.P. and M.M. we e inancially suppo ed by he Compe i i e S a e Resea ch Financing o he Expe
Responsibili y A ea o Tampe e Uni e si y Hospi al, G an No. 9V041.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
Nu ien s 2019,11, 320 8 o 12
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