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