ORIGINAL ARTICLE: Clinical Endoscopy

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Mapping histologic patchiness of celiac diseaseby push enteroscopy

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Francesco Valitutti, MD,1 Giovanni Di Nardo, MD,1 Maria Barbato, MD,1 Marina Aloi, MD, PhD,1

Ilaria Celletti, MD,1 Chiara Maria Trovato, MD,1 Maria Pierdomenico, PhD,2 Adriana Marcheggiano, MD,3

Salvatore Cucchiara, MD, PhD1

Rome, Italy

Background: Despite great improvements in serologic testing, duodenal biopsies are still required to diagnosethe majority of celiac disease (CD) cases. Nevertheless, the histologic pattern of CD is often patchy, leading to therisk of missing the diagnosis.

Objective: To evaluate the patchiness of the CD histologic lesions along the small bowel (SB), push enteroscopyhas been performed instead of conventional upper GI endoscopy.

Design: Prospective, single-center study.

Setting: Tertiary-care referral center.

Patients: A total of 41 pediatric patients with suspected CD.

Intervention: Prospective evaluation of bulb, duodenal, and jejunal biopsy specimens in the diagnosisof CD.

Main Outcome Measurements: Pattern of lesion distribution along the SB (from bulb up to 60 cm beyond theligament of Treitz) and yield as well accuracy of pediatric CD diagnosis by using push enteroscopy.

Results: There was a homogeneous pattern of histologic damage in 17 patients (41.5%), whereas 24 patients(58.5%) had a lesion pattern of patchiness. The second and fourth duodenal regions were involved in 38 children(92.7%) and 37 children (90.2%), respectively; the bulb was involved in 37 patients (90.2%); both distal and prox-imal jejunal samples showed histologic lesions in 38 children (92.7%). In 1 patient, without lesions in the bulband duodenum, CD was diagnosed according to proximal and distal jejunal biopsies only (3B and C, respec-tively). A significant correlation was found between the degree of villous atrophy and the serum anti-transglutaminase titer.

Limitations: Small sample size; academic tertiary-care setting.

Conclusion: CD histologic lesions often have a discontinuous distribution along the SB, occasionally with anexclusive jejunal involvement. A high degree of villous atrophy correlates with a high anti-transglutaminasetiter. When the new ESPGHAN “biopsy-sparing” criteria are not applicable, in case of potential CD, push en-teroscopy might be a valuable second-step tool to re-evaluate and identify false “potential” CD hiding exclusivejejunal lesions. (Gastrointest Endosc 2014;79:95-100.)

ns: CD, celiac disease; ESPGHAN, The European Societytric Gastroenterology Hepatology and Nutrition; MO,huber.

E: All authors disclosed no financial relationships relevantcation.

2014 by the American Society for Gastrointestinal Endoscopy36.00i.org/10.1016/j.gie.2013.06.012

vember 17, 2012. Accepted June 17, 2013.

Current affiliations: Pediatric Gastroenterology and Liver Unit, Departmentof Pediatrics, Sapienza University of Rome, Rome (1), ENEA, Italian NationalAgency for new Technologies, Energy and Sustainable EconomicDevelopment, Rome (2), Department of Clinical Science, SapienzaUniversity of Rome, Rome, Italy (3).

Reprint requests: Salvatore Cucchiara, MD, PhD, Department of Pediatrics,Director Pediatric Gastroenterology & Liver Unit, Head SapienzaUniversity of Rome, University Hospital Umberto I, Rome Viale ReginaElena 324 - 00161 Rome, Italy.

urnal.org Volume 79, No. 1 : 2014 GASTROINTESTINAL ENDOSCOPY 95

Celiac disease and push enteroscopy Valitutti et al

Celiac disease (CD) is a permanent immune-mediated sys-temic disorder triggered by gluten, a storage protein of wheatand related cereals, in genetically susceptible individuals. It ischaracterized by different clinical manifestations, CD-specificantibodies (anti-transglutaminase and anti-endomysial anti-bodies), human leukocyte antigen (HLA-DQ2 and/or DQ8haplotypes), and different degrees of enteropathy.1 In CD,the ingestion of gluten activates an aberrant immuneresponse leading to progressive damage of the small-intestine mucosa and impaired small-bowel absorptivefunctions and tomedium-termand long-termadverse events.2

Except for selected symptomatic cases in the pediatricpatient with high titers of CD-related antibodies andcompatible human leukocyte antigen typing, the diagnosisof CD still relies on multiple duodenal biopsy specimensobtained by upper GI endoscopy.1 Because it has beenwidely described that the histologic pattern of CD isoften patchy, multiple biopsies are mandatory to reducethe risk of missing the diagnoses.3,4 Histologic lesions ofCD may vary notably from site to site; moreover, some au-thors highlighted that different degrees of severity may befound even within the same biopsy specimen.5

The current European Society of Pediatric Gastroenter-ology, Hepatology and Nutrition (ESPGHAN) statement ad-vises taking at least 4 biopsy specimens from the secondand/or third portion of the duodenum and at least 1 fromthe duodenal bulb.1 However, the debate on where toperform biopsies still animates the medical community.Because it has been reported that histologic damage maybe confined to the duodenal bulb,6-8 it has been recom-mended to obtain 4 biopsy specimens from the bulb and 4from the duodenum in order to increase the diagnostic yield,9

but this finding has not been confirmed by others10;moreover, a survey has emphasized a wide gap betweenrecommendations and clinical practice, showing that evenexperienced endoscopists were reluctant to take more than4 duodenal biopsy specimens for the diagnosis of CD.11 Itwas also reported that villous atrophy may be merelypresent in the jejunum.12-14

Therefore, we aimed to further evaluate the patternof distribution of the histologic lesions along the small bowelin a pediatric cohort of CDpatients at diagnosis by using pushenteroscopy instead of conventional upper GI endoscopy.

MATERIALS AND METHODS

Fifty-seven pediatric patients with suspected CD werereferred to the Pediatric Gastroenterology and Liver Unitof the Sapienza University in Rome from May 2011 toJuly 2012. During the whole recruiting period (14 months),41 CD patients were recruited for the experimental proto-col, whereas 16 patients were not included in the study(9 patients underwent conventional upper GI endoscopybecause of parental denial of the research protocol, and7 were not confirmed by intestinal biopsy for clinical rea-sons or parental denial).

96 GASTROINTESTINAL ENDOSCOPY Volume 79, No. 1 : 2014

Take-home Message

� This study has investigated the possible implication ofpush enteroscopy in the diagnosis of pediatric celiacdisease.

� This study stimulates the debate on which small-bowelsites the endoscopic biopsies should be performed inorder to identify histologic lesions and, thus, to confirmthe diagnosis. Moreover, it might introduce a novel andsecond-step diagnostic approach to so-called potentialceliac disease.

All 41 of the recruited patients (15 boys, aged from 1.6-15.1 years) were gluten-free naïve, on a long-lasting,gluten-containing diet; none of them had been previouslydiagnosed with CD. All patients had positive test results foranti-transglutaminase antibodies and strong positivity foranti-endomysial antibodies.

The study protocol for the experimental use of push en-teroscopy in the diagnosis of CD had been previouslyapproved by the Ethics Committee of University Hospital.Before recruitment, both the study and the procedure writ-ten consent were obtained from all parents and patientswhen applicable, after thorough explanations of theresearch protocol and the differences with standard clinicalpractice. Conventional upper GI endoscopy was offered atthe same time as a standard and comprehensive procedurefor diagnosis.

Push enteroscopy was performed with patients undergeneral anesthesia and by using Olympus Enteroscope SIF180 Q without overtube and Olympus Endojaws disposableforceps Model FB 230V (Olympus, Hamburg, Germany).A single endoscopist performed all 41 procedures. Theenteroscope was introduced to 60 cm distally from theligament of Treitz, with a mean procedure duration compa-rable to conventional upper GI endoscopy under generalanesthesia. Standard biopsy specimens were taken from 5different sites (1 biopsy per site): bulb, second, and fourthduodenal regions, proximal and distal jejunum (30 cm and60 cm beyond the ligament of Treitz, respectively). In eachregion, biopsy specimens were obtained where endoscopicfindings (“cobblestone” mucosa, scalloping) were present;when no endoscopic feature was altered, small-bowel spec-imens were randomly collected in each site. All sampleswere carefully oriented on acetate cellulose filters andsent to the same expert GI tract pathologist, who was awareof the clinical indication to the small-bowel biopsy butblinded both to endoscopic features and sampling sites.Specimens were graded according to the Marsh-Oberhuber (MO) criteria (in brief: MO 0Z normal mucosa;MO 1 Z increased number of intraepithelial lymphocytes;MO 2Z crypt hyperplasia; MO 3aZ partial villous atrophy;MO 3b Z subtotal villous atrophy; MO 3c Z total villousatrophy).

Relative patchiness was defined as the presence, in thesame patient, of a certain degree of lesion in 1 site and a

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TABLE 1. Clinical features summarized as typical (withGI symptoms), atypical (with extraintestinal symptoms),and silent (with no symptoms)

Age, y Typical CD Atypical CD Silent CD

!2 4 0 2

O2-6 9 1 10

O6-10 7 2 2

O10 2 0 2

CD, Celiac disease.

Valitutti et al Celiac disease and push enteroscopy

different MO degree of lesion in another site (eg, MO 2 atthe bulb; MO 3a at the second duodenal section). Absolutepatchiness was defined instead as the presence, in the samepatient, of a lesion in 1 site and its absence in another site(eg, no lesion at the second duodenal section; MO 3c at thedistal jejunum). Within-lesion variability also was studied.

Thedistribution frequencyof histologic lesions indifferentbiopsy sites and their presumptive associations with clinical(sex; age at diagnosis; symptomatic vs silent CD; typical vsatypical CD), serologic (serumanti-transglutaminase titer; an-tibodies to deamidated gliadin peptides titer, when available),and endoscopic data (cobblestonemucosa, scalloping, or lossof duodenal folds) were statistically evaluated by using the c2

test and the Fisher exact test when applicable.

TABLE 2. Clinical features of recruited patients

Clinical featuresNo. ofpatients

Family screening 15

Failure to thrive 8

Recurrent abdominal pain 6

Diarrhea 6

Alopecia areata 1

Type 1 diabetes mellitus 1

Type 1 diabetes mellitus þ Hashimoto’sthyroiditis

1

Constipation 1

Bloating 1

Iron deficiency anemia 1

RESULTS

Clinical features of all recruited patients are summarizedin Table 1 and Table 2. Seventeen patients (41.5%;95% confidence interval [CI], 27.7-55.2) showed ahomogeneous pattern of histologic damage, with the sameMO grade in all sites, whereas 24 (58.5%; 95% CI, 43.5-73.5) had a patchy pattern of lesions, that was relative in16 (41.4%) and absolute in 8 (19.5%), respectively. Inaddition, 3 patients also displayed a certain degree ofvariability within the same biopsy specimen.

The second and the fourth duodenal samples revealedhistologic damage in 38 (92.7%; 95% CI, 87-96) and 37(90.2%; 95% CI, 81.0-99.2) patients, respectively; villous atro-phy, ranging from grade 3a to 3c, was overall represented in90.2% and 85.3% of patients. Bulb samples were abnormal in37 cases (90.2%; 95% CI, 81.0-99.2), most of which had se-vere grading (3c þ 3b þ3a: 90%). No patient showed exclu-sive bulbar abnormalities.

On the other hand, both proximal and distal jejunalsamples showed histologic lesions in 38 patients (92.7%;95% CI, 87-96), more frequently with a severe lesion de-gree (3c þ 3b þ 3a: 92.7% in both the distal and proximaljejunum). In 1 patient without lesions in the bulb and du-odenum, the diagnosis of CD was confirmed by proximaland distal jejunal biopsies only. This patient showed ananti-transglutaminase titer of 67 U/mL (Eurospital, Trieste,Italy) and a strong positive pattern at EmA immunofluores-cence. With regard to his endoscopic features, the patientshowed normal-appearing mucosa in the duodenum,whereas he showed cobblestone and scalloped mucosain the jejunum. His histopathologic specimens weregraded as follows: bulb (no lesion); second duodenal re-gion (no lesion); fourth duodenal region (no lesion); prox-imal jejunum (MO 3b); distal jejunum (MO 3c).

The distribution of histologic lesions is represented inFigure 1. Overall, no significant difference of severity hasbeen disclosed among the studied regions.

There was no significant correlation between thepattern of lesion distribution (both relative and absolute

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patchiness) and several clinical (sex, age at diagnosis,symptomatic vs silent CD, typical vs atypical CD), serologic(serum anti-transglutaminase titer; antibodies to deami-dated gliadin peptides titer, when available), and endo-scopic data (cobblestone mucosa, scalloping, or loss ofduodenal folds). The endoscopic features of the studiedpatients are represented in Figure 2.

A correlation was found between severity of villousatrophydin particular 3cdand the level of serum anti-transglutaminase titer (Pearson c2 test Z 9.057 with a Z0.01 and d.f. Z 1; p Z .003).

DISCUSSION

CD exhibits different histologic abnormalities, rangingfrom increased intraepithelial lymphocyte count withnormal villous architecture to total villous atrophy. In CDhistology, patterns of abnormalities mainly include partialto total villous atrophy, elongated crypts, decreased villusto crypt ratio, and increased intraepithelial lymphocyte

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Figure 1. Distribution of histological lesions among studied patients. D2, second duodenal region; D4, fourth duodenal region;MO, Marsh-Oberhuber scale.

Figure 2. Endoscopic features of studied patients.

Celiac disease and push enteroscopy Valitutti et al

density.15 In addition, an absence of an identifiable brushborder may be seen in addition to abnormalities in theepithelial cells, which become flattened, cuboid, andpseudostratified. According to the Marsh classification,lesions include infiltrative, hyperplastic, and atrophicpatterns.16 This preliminary classification was modified byOberhuber et al,17 and later by Corazza and Villanacci,18

whose attempt has achieved a better agreement amongdifferent observers. However, the most used classificationfor CD lesions is still MO grading, which takes intoaccount most of the histologic features described in CD.

Some individuals with positive CD serology results mayexhibit a normal mucosa when duodenal biopsy specimensare obtained by upper GI endoscopy. Such patients arecommonly labelled as “potential celiac,” and many ofthem can later develop the typical lesions of CD.19

Analysis of multiple biopsy specimens is critical. Patchi-ness of the lesions has been reported by several authors,20,21

and a recent study has reported that different degrees oftissue damage may be present even in the same biopsy.10

Moreover, where to perform endoscopic biopsies is still amatter of discussion. In some patients, lesions may beconfined to the duodenal bulb only,20,21 whereas other au-thors suggested the possibility of an exclusive distal jejunaldamage.12-14

The current ESPGHAN guidelines for CD recommendthat biopsy samples should be obtained from the secondand/or third portion of the duodenum (at least 4 specimens)and from the duodenal bulb (at least 1 sample),1 butno statement is provided on the utility of jejunal sampling.

For many years, investigating the small bowel along itsentirety has been just a fascinating dream for gastroenterol-ogists. First, the introduction of wireless capsule endoscopy

98 GASTROINTESTINAL ENDOSCOPY Volume 79, No. 1 : 2014

widened perspectives in the study of the so-called midgut; subsequently, the advent of push enteroscopy, whichpermits tissue sampling, considerably enlarged diagnosticyields.22 Currently, enteroscopy has both diagnostic andtherapeutic applications, and the list of its indications isconstantly being extended. Obscure GI bleeding, intestinalstrictures, retained foreign bodies, and small-bowel polypsrepresent the most common conditions requiring furtherevaluation by using enteroscopy.23 In adults with CD it isused as an alternative to wireless capsule endoscopy, forassessing the refractory forms and their complications(collagenous sprue, small-bowel carcinoma, enteropathy-type T-cell lymphoma).24 However, similarly to wirelesscapsule endoscopy, its definite role in diagnosing CDremains unsettled.25,26

In this study, we aimed to investigate both the histolog-ic patchiness in small-bowel mucosa of CD patients and

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Valitutti et al Celiac disease and push enteroscopy

whether there could be a suitable role for push entero-scopy in the diagnosis of CD. We examined 41 pediatric pa-tients with suspected CD by means of push enteroscopy,obtaining biopsy specimens both from the duodenum(bulb, second portion, and fourth portion) and from thejejunum (both 30 cm and 60 cm distally from the ligamentof Treitz). Like conventional upper GI endoscopy at ourcenter, the procedure was performed with the patient un-der general anesthesia and was not more time-consumingthan conventional endoscopy with multiple biopsies,because of the limited tract of jejunum explored.

This approach has confirmed the prevalent patchy distri-bution of small-bowel histologic abnormalities, which hasbeen found in the majority of cases (58.5%). A total of 16 pa-tients showed a relative patchy pattern, that is, different MOdegree of lesion (fromMO 1 to MO 3c) along the duodenumand the jejunum. Conversely, 8 patients presented CD le-sions at some sites, whereas other regions did not showany feature of histologic damage and appeared completelynormal (absolute patchy pattern). As documented by otherauthors,10 it was not uncommon in our series to identify acertain degree of variability within the same biopsyspecimen, as seen in 3 patients of our population.

Duodenal sampling without the bulb would have al-lowed confirmation of the diagnosis of CD in 38 cases(92.7%). When also considering bulb biopsies, whichwere involved in 37 patients (90.2%), the diagnostic yieldslightly increased. Indeed, 40 patients showed overallduodenal abnormalities at histology (bulb plus secondand fourth duodenal sites). Nevertheless, bulb mucosawas never exclusively involved: jejunal mucosal damagehas constantly been coupled with the bulbar lesions. Itmay be possible that the very early histologic damage inCD is confined to the bulb, as underscored for patientsstarting a gluten challenge in a different study.6 However,it is conceivable that our results, always addressing thebulbar-jejunal association of lesions, could be attributedto the fact that all patients were recruited at diagnosisand were on a long-lasting gluten-containing diet. Regard-less, discrepancies with other studies remain.7,8 As sug-gested by other authors, sampling biopsies more distallyin the jejunum may decrease the likelihood of confusinghistologic findings because the jejunal mucosa is less proneto unspecific damage induced by luminal acid content.27

It is noteworthy to observe that in 1 boy, referredbecause of iron-deficiency anemia and CD-associated anti-bodies (anti-transglutaminase: 67 U/mL [normal values,0-16 U/mL]; strong positivity for anti-endomysial anti-bodies), no lesion in the bulb and duodenum could befound: in this case, the diagnosis of CD was confirmedby proximal and distal jejunal biopsies (MO grade 3b and3c, respectively). Intriguingly, this patient would not haveachieved the CD diagnosis without jejunal biopsies andwould have been classified as potential CD. It is temptingto speculate that the entity known as potential CD mightoften hide distal lesions.

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Another finding of this study concerns a specificserologic-histologic correlation. It has been previouslydescribed that a high serum anti-transglutaminase titer isrobustly specific for duodenal atrophy, both in childrenand adults.28-30 We were able to highlight a correlation be-tween the highest levels of serum anti-transglutaminasetiter (O100 UI/dL) and villous atrophy, in particular thehighest degree (MO 3c). These data are in accordancewith the new guidelines statements.1

However, our study has some limitations. First, becausewe had a small sample size, we should not overemphasizeour findings. We are aware that further studies are neededon this issue before drawing definite conclusions on theopportunity to use push enteroscopy to confirm uncertainCD diagnoses. Second, we ran the study in an academictertiary-care setting, where push enteroscopy is available:this is definitely not the case of many other hospitalsworldwide, and therefore this limits the applicability ofour protocol to very few tertiary-care centers.

In conclusion, this study has investigated the possibleimplication of push enteroscopy in the diagnosis of pediatricCD. Moreover, it stimulates the debate about which small-bowel sites the endoscopist should use in order to identifyhistologic lesions and, thus, to confirm the diagnosis. Basedon our study, push enteroscopy in the diagnosis of CDcould be reserved to patients with positive but low titerserum anti-transglutaminase antibodies and apparentlynormal histology at initial conventional upper GI endos-copy. Therefore, when the new ESPGHAN “biopsy-sparing”criteria1 are not applicable, push enteroscopy might be avaluable second-step tool both to redirect the diagnosisand to identify false potential CD hiding exclusive jejunallesions. However, further studies on larger patient cohortsare needed to confirm the usefulness of this new diagnosticapproach to potential CD.

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