Limitations of faecal calprotectin in detecting histological changes and persistent villous atrophy in patients with coeliac disease on a gluten-free diet

Alimen a y Pha macology & The apeu ics, 2025; 61:1815–1819
h ps://doi.o g/10.1111/ap .70114
1815
Alimen a y Pha macology & The apeu ics
RESEARCH COMMUNICATION OPEN ACCESS
Limi a ions o Faecal Calp o ec in in De ec ing His ological
Changes and Pe sis en Villous A ophy in Pa ien s Wi h
Coeliac Disease on a Glu en- F ee Die
Ve ónicaSegu a1 | ÁngelaRuiz-Ca nice 1 | ÁngelesPiza o2 | Ca menGonzález-Na anjo2 |
JacoboDíaz3 | C is óbalCo onel-Rod íguez4 | Fede icoA güelles-A ias5 | Ma aGa zón-Bena ides2 |
Ca olinaSousa1 | IsabelComino1
1Depa men o Mic obiology and Pa asi ology, Facul y o Pha macy, Uni e si y o Se ille, Se ille, Spain | 2Diges i e Disease Clinical Uni and CIBERehd,
Ins i u e o Biomedicine o Se ille (IBiS), SeLi e G oup, Vi gen del Rocío Hospi al/CSIC/US, Se ille, Spain | 3Clinical Analysis Se ice, Hospi al
Uni e si a io INGESA, Ceu a, Spain | 4Cen o de Salud Aman e La ón, Se ille, Spain | 5Diges i e Diseases Clinical Uni , Depa men o Medicine,
Facul y o Medicine, Vi gen Maca ena Hospi al, Uni e si y o Se ille, Se ille,Spain
Co espondence: Isabel Comino ([email protected])
Recei ed: 7 Feb ua y 2025 | Re ised: 26 Feb ua y 2025 | Accep ed: 22 Ma ch 2025
Handling Edi o : Jason A Tye- Din
Funding: This wo k was suppo ed by G an PI- 0053- 2018 p o ided by Jun a de Andalucía (Fundación Pública Andaluza P og eso y Salud, Spain).
Keywo ds: coeliac disease| aecal calp o ec in| his ological changes| illous a ophy
ABSTRACT
Faecal calp o ec in is used o assess in es inal in lamma ion, bu i s ole in moni o ing mucosal healing in coeliac disease is
unclea . This s udy ollowed 48 adul s wi h coeliac disease on a glu en- ee die o e 12 mon hs, e alua ing aecal calp o ec in
le els in co ela ion wi h an i- ansglu aminase an ibodies, glu en- ee die adhe ence by die a y ques ionnai es and his ology.
Al hough signi ican his ological lesions (Ma sh II–III) dec eased om 24% o 10%, aecal calp o ec in le els luc ua ed wi hou
co ela ion o an i- ansglu aminase, adhe ence o his ological emission, and did no di e en ia e be ween lesion g ades. Ou
indings unde sco e aecal calp o ec in's un eliabili y in moni o ing mucosal healing in adul s wi h coeliac disease, highligh ing
he u gen need o al e na i e bioma ke s.
1 | In oduc ion
Coeliac disease is a sys emic au oimmune diso de igge ed
by glu en pep ides, which elici a T cell–media ed immune e-
sponse, esul ing in small in es inal illous a ophy and ch onic
in lamma ion [1]. A li elong glu en- ee die is he mains ay o
coeliac disease ea men , imp o ing symp oms and in es inal
lesions while p e en ing long- e m complica ions. Howe e , pe -
sis en illous a ophy may occu in some pa ien s despi e ollow-
ing a glu en- ee die , commonly due o poo die a y adhe ence,
delayed mucosal esponse o ongoing glu en sensi i i y [2].
As in o he ch onic in es inal diso de s, e ec i e moni o ing o
coeliac disease equi es ools ha accu a ely e lec mucosal s a-
us. Al hough in es inal biopsy is he gold s anda d, ou ine ac-
quisi ion o se ial in es inal biopsies is hinde ed by in asi eness,
high cos and inhe en isks. An i- issue ansglu aminase IgA
an ibodies a e sensi i e o diagnosis bu lose eliabili y a e di-
agnosis due o poo co ela ion wi h his ology in pa ien s on a
glu en- ee die [3]. Fu he mo e, symp oms and die a y ques-
ionnai es a e un eliable [4], unde sco ing he need o objec-
i e, non- in asi e bioma ke s o assess in es inal in lamma ion
in coeliac disease.
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© 2025 The Au ho (s). Alimen a y Pha macology & The apeu ics published by John Wiley & Sons L d.
1816 Alimen a y Pha macology & The apeu ics, 2025
Faecal calp o ec in is a neu ophil- de i ed p o ein eleased in o
he gu du ing in lamma o y p ocesses [3]. I s esis ance o enzy-
ma ic deg ada ion ensu es s abili y and easy measu emen o e
ime. Clinically, aecal calp o ec in is aluable because i educes
unnecessa y endoscopic p ocedu es, and se e al comme cially
a ailable me hods exis o i s measu emen [5]. Ele a ed ae-
cal calp o ec in le els a e associa ed wi h in lamma o y bowel
disease, colo ec al cance , non- s e oidal an i- in lamma o y
d ug en e opa hy, ch onic panc ea i is and ci hosis, al hough
e idence ou side in lamma o y bowel disease emains lim-
i ed [6]. In in lamma o y bowel disease, aecal calp o ec in is a
well- es ablished non- in asi e bioma ke in adul s and child en.
Howe e , i s ole in coeliac disease emains unclea [7]. Some
s udies ha e shown ha ele a ed aecal calp o ec in le els in
paedia ic pa ien s newly diagnosed wi h coeliac disease no -
malise on a glu en- ee die ; o he s epo ed no signi ican co -
ela ion be ween aecal calp o ec in le els, clinical symp oms o
his ological indings. These disc epancies unde line he need o
addi ional esea ch on he ole o aecal calp o ec in in manag-
ing coeliac disease.
We aimed o e alua e aecal calp o ec in le els sys ema ically
o e ime in adul pa ien s wi h coeliac disease adhe ing o a
glu en- ee die o a leas 24 mon hs. Speci ically, we com-
pa ed aecal calp o ec in le els wi h se ological ma ke s and
glu en- ee die adhe ence es s, while assessing hei co ela-
ion wi h duodenal his ology h ough biopsies a baseline and
12 mon hs. Th ough his analysis, we sough o de e mine he
po en ial u ili y o aecal calp o ec in as a non- in asi e bio-
ma ke o moni o ing disease ac i i y and mucosal s a us in
coeliac disease.
2 | Me hods
We conduc ed a longi udinal p ospec i e s udy on aecal cal-
p o ec in de ec ion in pa ien s wi h coeliac disease on a glu en-
ee die o a leas 24 mon hs be ween June 2019 and Ma ch
2023. Pa icipan s had s udy isi s a inclusion and a 3, 6 and
12 mon hs, whe e clinical examina ions, blood sampling o
coeliac disease se ology and s ool collec ion o aecal calp o-
ec in quan i ica ion we e pe o med. They also comple ed a
glu en- ee die adhe ence ques ionnai e. Duodenal biopsies
we e ob ained a he ime o inclusion and a e 12 mon hs o
assess lesion p og ession. The s udy p o ocol was app o ed by
he e hics commi ee o each ins i u ion, and w i en in o med
consen was ob ained om all he pa icipan s.
Faecal calp o ec in le els we e measu ed wi h he Bühlmann
CAL ELISA ki and ca ego ised as > 200 μg/g (mode a e/
se e e in lamma ion), 50–200 μg/g (mild in lamma ion)
and < 50 μg/g (no in lamma ion). Endoscopic biopsies we e
g aded his ologically using he Ma sh–Obe hube classi ica-
ion. A bo h baseline and 1- yea ollow- up endoscopies, ou
duodenal biopsies we e ob ained om he second po ion o
he duodenum. His ological e alua ion was pe o med inde-
penden ly by expe pa hologis s, based on he mos se e e
lesion iden i ied among he samples; a ophy was u he
classi ied as o al, sub o al o ocal. His ological e olu ion
was assessed by compa ing he wo epo s. In aepi helial
lymphocy es we e quan i ied using he Ven ana BenchMa k
ULTRA and CD3 an ibodies (Roche Holding AG). An i- issue
ansglu aminase IgA le els we e assessed using he EliA
Celikey IgA/IgG ki s, and adhe ence o a glu en- ee die was
e alua ed using he Spanish e sion o he Celiac Die a y
Adhe ence Tes .
Sample size was calcula ed wi h a 95% con idence le el (α = 0.05),
80% powe (β = 0.2) and an expec ed p opo ion o 0.5, adjus ed
o a 10% loss a e, esul ing in 40 pa icipan s (GRANMO 8.0
ool). S a is ical analysis included no mali y es s and empo al
measu emen compa isons using Coch an's Q, Mann–Whi ney
U, F iedman, and Wilcoxon signed- ank es s. Da a we e an-
alysed wi h SPSS ( 29), wi h p < 0.05 conside ed s a is ically
signi ican .
3 | Resul s
3.1 | Pa ien s
We included 48 pa ien s; se en we e excluded due o missing
s ool samples o ollow- up isi s. Thus, 41 pa ien s (33 women)
wi h a median age o 34 yea s (in e qua ile ange [IQR]: 20.5–
47.5) comple ed he s udy.
3.2 | Clinical, Analy ical and His ological
E olu ion o Pa ien s Du ing Follow- Up
A inclusion, 24% o pa ien s (10/41) had signi ican Ma sh II–
III his ological lesions despi e ollowing a glu en- ee die o a
leas 24 mon hs. This p opo ion dec eased o 10% (4/39) a e
12 mon hs. His ology emained s able wi hou mucosal damage
in 29 pa ien s om inclusion o he 12- mon h ollow- up (Ma sh
0–I). Six pa ien s showed his ological imp o emen , wi h muco-
sal damage esol ing by 12 mon hs (Ma sh II–III o Ma sh 0–I).
In con as , mucosal damage pe sis ed in h ee pa ien s (Ma sh
II–III o Ma sh II–III), while one expe ienced his ological p o-
g ession (Ma sh 0–I o Ma sh II–III).
The p opo ion o non- adhe en pa ien s, as measu ed by he
Celiac Die a y Adhe ence Tes , emained s able (33% a inclu-
sion, 32% a 12 mon hs). Analysis o an i- ansglu aminase an-
ibody analysis showed ha 10% o pa ien s (4/41) had ele a ed
concen a ions (> 10 U/mL) a inclusion, which dec eased o 5%
(2/39) a 12 mon hs. Median an i- issue ansglu aminase le -
els emained below he 10 U/mL h eshold h oughou he ol-
low- up pe iod.
To inclusion, 35% o pa ien s (14/40) had aecal calp o ec in
> 50 μg/g, including 10% (4/40) wi h alues > 200 μg/g. These
p opo ions emained s able a 3 mon hs (36% and 10%). By
6 mon hs, aecal calp o ec in > 50 μg/g inc eased o 51% (20/39),
while aecal calp o ec in > 200 μg/g emained a 13% (5/39). A
12 mon hs, 46% (18/39) had aecal calp o ec in > 50 μg/g, wi h
10% (4/39) exceeding 200 μg/g. Median aecal calp o ec in le els
inc eased om 30.70 μg/g a inclusion o 39.50 μg/g a 12 mon hs,
bu no s a is ically signi ican di e ences we e obse ed ac oss
ollow- up isi s (Figu e1).
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3.3 | Analysis o Conco dance Be ween Di e en
Coeliac Disease Bioma ke s Du ing Follow- Up
3.3.1 | Faecal Calp o ec in, An i- issue
T ansglu aminase and Celiac Die a y Adhe ence
Tes Sco es
We e alua ed he ela ionship be ween aecal calp o ec in le -
els and ci cula ing an i- issue ansglu aminase le els ac oss
isi s using he Spea man co ela ion coe icien (ρ). We ound
no signi ican co ela ion, sugges ing ha luc ua ions in ae-
cal calp o ec in do no co ela e wi h changes in an i- issue
ansglu aminase le els, indica i e o an immune esponse o
glu en (Figu eS1). Simila ly, no signi ican associa ion was ob-
se ed be ween aecal calp o ec in le els and he Celiac Die a y
Adhe ence Tes sco es.
3.3.2 | An i- issue T ansglu aminase, Celiac Die a y
Adhe ence Tes and Ma sh Sco e
No pa ien s wi h Ma sh II–III lesions had an i- issue ansglu-
aminase concen a ions abo e he h eshold, indica ing no
co ela ion be ween an i- issue ansglu aminase le els and
mucosal damage (Mann–Whi ney U es , p > 0.05). No ably,
all pa ien s wi h an i- issue ansglu aminase > 10 U/mL e-
mained wi hou mucosal damage (Ma sh 0–I) (Figu e2a–c).
Addi ionally, Coch an's Q es (p > 0.05) showed no sig-
ni ican associa ion be ween his ological p og ession and
glu en- ee die adhe ence, as assessed by he Celiac Die a y
Adhe ence Tes .
3.3.3 | Faecal Calp o ec in and Ma sh Sco e
In he 29 pa ien s wi hou mucosal damage, median aecal cal-
p o ec in le els emained below 50 μg/g a all isi s. Among he
six pa ien s achie ing his ological emission (Ma sh II–III o
Ma sh 0–I), aecal calp o ec in le els inc eased o e 12 mon hs
(median: 39.55 μg/g a inclusion; 78.90 μg/g a 12 mon hs), al-
hough his was no s a is ically signi ican (F iedman es ,
p > 0.05). In con as , aecal calp o ec in le els dec eased in he
h ee pa ien s wi hou emission (Ma sh II–III o Ma sh II–III)
(median: 43.6–28.2 μg/g). One pa ien p og essing om Ma sh
0–I o Ma sh II–III showed an inc ease om 40.3 o 89 μg/g
(Figu e2d– ).
4 | Discussion
This s udy highligh s he limi a ions o aecal calp o ec in as
a bioma ke o moni o ing his ological eco e y in adul pa-
ien s wi h coeliac disease on a glu en- ee die . The lack o
signi ican changes in aecal calp o ec in le els, e en in pa-
ien s wi h his ological imp o emen , unde sco es i s limi ed
sensi i i y in e lec ing mucosal egene a ion. Simila ly, coe-
liac disease se ology and he Celiac Die a y Adhe ence Tes
sco e also ailed o de ec meaning ul imp o emen s in mu-
cosal eco e y.
In con as , some s udies in bo h paedia ic and adul popu-
la ions ha e sugges ed ha aecal calp o ec in le els dec ease
ollowing he ini ia ion o a glu en- ee die and co ela e wi h di-
e a y adhe ence, pa icula ly in pa ien s wi h a gas oin es inal
FIGURE 1 | E olu ion o his ological lesions, se ological ma ke s, Celiac Die a y Adhe ence Tes sco es and aecal calp o ec in le els a inclu-
sion and a subsequen ollow- up isi s (3, 6 and 12 mon hs). Pe cen age o pa ien s wi h di e en bioma ke s assessed a inclusion and a subse-
quen ollow- up isi s (3, 6 and 12 mon hs). Faecal calp o ec in le els we e in e p e ed acco ding o he manu ac u e 's ecommended cu - o , which
> 200 μg/g sugges s in lamma ion anging be ween mode a e o se e e and 50–200 μg/g may indica e mild o ganic diso de s. An i- TG, an i- issue
ansglu aminase an ibody; CDAT, coeliac die a y adhe ence es ; FC, aecal calp o ec in.
13652036, 2025, 11, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ap .70114 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [26/05/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
1818 Alimen a y Pha macology & The apeu ics, 2025
p esen a ion o he disease [8–10]. These s udies suppo a po-
en ial ole o aecal calp o ec in in moni o ing esponse o
ea men . Howe e , we did no obse e such associa ions in
adul s, which may e lec a ia ions in disease se e i y, du a ion
o di e ences in s udy design.
Con e sely, nume ous s udies ha e ailed o es ablish a sig-
ni ican ela ionship be ween aecal calp o ec in le els and
his ological ou comes in coeliac disease. Speci ically, se e al
s udies ha e shown no co ela ion be ween aecal calp o ec in
le els and he se e i y o in es inal lesions o clinical p esen a-
ion [11]. Addi ionally, o he esea ch has ound no signi ican
di e ences in aecal calp o ec in le els be ween adul coeliac
disease pa ien s and heal hy con ols, u he limi ing i s u ili y
in moni o ing disease ac i i y[12]. Consis en wi h hese ind-
ings, ou esul s demons a ed ha aecal calp o ec in le els
did no co ela e wi h Ma sh sco es and emained s able o e
ime, e en in pa ien s achie ing his ological emission. No ably,
some pa ien s who imp o ed his ologically showed an inc ease
in aecal calp o ec in le els, while o he s wi h pe sis en mu-
cosal damage expe ienced a decline, ein o cing he a iabili y
and lack o p edic i e alue o aecal calp o ec in in his con-
ex . This sugges s a disconnec be ween aecal calp o ec in and
mucosal eco e y. Suppo ing his iew, he ESPGHAN expe
g oup ecommended agains using aecal calp o ec in o coe-
liac disease diagnosis o moni o ing in paedia ic pa ien s [13].
The obse ed inc ease in aecal calp o ec in le els a 12 mon hs
in pa ien s wi h his ological emission may e lec esidual o
low- g ade in lamma ion ha his ology does no ully cap u e,
suppo ing he obse a ion ha aecal calp o ec in can de ec
subclinical in lamma ion [14]. Howe e , he lack o s a is ical
signi icance in ou F iedman's es highligh s he need o la ge
s udies o con i m hese indings. Ele a ed aecal calp o ec in
le els in his ological emission may also sugges o he unde ly-
ing gas oin es inal condi ions o ac o s in luencing in es inal
in lamma ion, u he complica ing he in e p e a ion o aecal
calp o ec in in coeliac disease.
In conclusion, ou s udy highligh s he limi a ions o aecal
calp o ec in as a eliable bioma ke o moni o ing his ological
changes in coeliac disease. The in e p e a ion o aecal calp o-
ec in le els is complica ed by a iabili y in in lamma o y e-
sponses and he p esence o subclinical condi ions, emphasising
he need o conside addi ional ac o s. These indings ein-
o ce he challenges o using aecal calp o ec in as a s andalone
bioma ke and unde sco e he need o mo e accu a e non-
in asi e ma ke s o assessing mucosal s a us in coeliac disease
managemen .
Au ho Con ibu ions
Ve ónica Segu a: me hodology, alida ion, o mal analysis, da a cu-
a ion, w i ing – o iginal d a , w i ing – e iew and edi ing. Ángela
Ruiz- Ca nice : me hodology, alida ion, w i ing – e iew and edi -
ing, w i ing – o iginal d a , o mal analysis, da a cu a ion. Ángeles
Piza o: w i ing – e iew and edi ing, concep ualiza ion, me hod-
ology. Ca men González- Na anjo: w i ing – e iew and edi ing,
FIGURE 2 | Va ia ion o an i- ansglu aminase and aecal calp o ec in concen a ion le els in pa ien s wi hou illous a ophy du ing ollow- up
and in pa ien s who achie ed his ological emission a he end o he s udy. (a) An i- issue ansglu aminase concen a ion. (b) E olu ion o an i-
ansglu aminase le els in pa ien s wi hou illous a ophy du ing ollow- up. (c) E olu ion o an i- issue ansglu aminase le els in pa ien s who
achie ed his ological emission a he end o he s udy. (d) Faecal calp o ec in concen a ion. (e) E olu ion o aecal calp o ec in le els in pa ien s
wi hou illous a ophy du ing ollow- up. ( ) E olu ion o aecal calp o ec in le els in pa ien s who achie ed his ological emission a he end o he
s udy. The di e ences be ween pai ed g oups we e es ed wi h he F iedman and Wilcoxon es s. An i- TG, an i- issue ansglu aminase an ibody;
FC, aecal calp o ec in.
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1819
me hodology. Jacobo Díaz: o mal analysis, so wa e, w i ing – e iew
and edi ing. C is óbal Co onel- Rod íguez: w i ing – e iew and ed-
i ing, me hodology, concep ualiza ion. Fede ico A güelles- A ias:
concep ualiza ion, me hodology, w i ing – e iew and edi ing. Ma a
Ga zón- Bena ides: concep ualiza ion, me hodology, w i ing – e iew
and edi ing. Ca olina Sousa: p ojec adminis a ion, concep ualiza-
ion, in es iga ion, w i ing – o iginal d a , w i ing – e iew and edi ing,
isualiza ion, supe ision. Isabel Comino: concep ualiza ion, in es-
iga ion, unding acquisi ion, w i ing – o iginal d a , me hodology,
alida ion, isualiza ion, w i ing – e iew and edi ing, o mal analysis,
p ojec adminis a ion, so wa e, da a cu a ion, supe ision, esou ces.
Acknowledgemen s
We since ely hank D . Angel Cebolla o ideas con ibu ed o he
de elopmen o his p ojec . We hank he olun ee who en olled in
his s udy.
Con lic s o In e es
The au ho s decla e no con lic s o in e es .
Da a A ailabili y S a emen
The au ho s ha e no hing o epo .
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