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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:214–219

ORIGINAL ARTICLES—ALIMENTARY TRACT

Gastroesophageal Reflux Symptoms in Patients With Celiac Disease andthe Effects of a Gluten-Free Diet

FABIO NACHMAN, HORACIO VÁZQUEZ, ANDREA GONZÁLEZ, PAOLA ANDRENACCI, LILIANA COMPAGNI,HUGO REYES, EMILIA SUGAI, MARÍA LAURA MORENO, EDGARDO SMECUOL, HUI JER HWANG,INÉS PINTO SÁNCHEZ, EDUARDO MAURIÑO, and JULIO CÉSAR BAI

Department of Medicine, Dr C. Bonorino Udaondo Gastroenterology Hospital, Buenos Aires, Argentina

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BACKGROUND & AIMS: Celiac disease (CD) patientsften complain of symptoms consistent with gastroesophagealeflux disease (GERD). We aimed to assess the prevalence ofERD symptoms at diagnosis and to determine the impact of

he gluten-free diet (GFD). METHODS: We evaluated 133adult CD patients at diagnosis and 70 healthy controls. Fifty-three patients completed questionnaires every 3 months duringthe first year and more than 4 years after diagnosis. GERDsymptoms were evaluated using a subdimension of the Gastro-intestinal Symptoms Rating Scale for heartburn and regurgita-tion domains. RESULTS: At diagnosis, celiac patients had asignificantly higher reflux symptom mean score than healthycontrols (P � .001). At baseline, 30.1% of CD patients hadmoderate to severe GERD (score �3) compared with 5.7% ofcontrols (P � .01). Moderate to severe symptoms were signifi-cantly associated with the classical clinical presentation of CD(35.0%) compared with atypical/silent cases (15.2%; P � .03). Arapid improvement was evidenced at 3 months after initialtreatment with a GFD (P � .0001) with reflux scores compara-ble to healthy controls from this time point onward. CON-

LUSIONS: GERD symptoms are common in classicallyymptomatic untreated CD patients. The GFD is associatedith a rapid and persistent improvement in reflux symp-

oms that resembles the healthy population.

eywords: Celiac Disease; Gastroesophageal Reflux Disease; Glu-en-Free Diet; Clinical Outcome.

Celiac disease (CD) and gastroesophageal reflux disease(GERD) are common and distinct clinical conditions with

clearly different clinical and histological features and outcome.CD is an immune-mediated chronic inflammatory disorder dueto permanent gluten intolerance that mainly affects the smallbowel. It has an approximate prevalence of 1% in the westernhemisphere.1 The clinical presentations of CD vary tremen-dously among CD patients with a minority reporting gastroin-testinal symptoms and a large proportion of patients with fewgastrointestinal symptoms but numerous extraintestinal symp-toms. Some CD patients have few or no symptoms at all.2,3

GERD is a chronic condition that develops when the reflux

of stomach contents causes esophageal exposure to gastric

fluids.4 However, reflux of gastric acid is not the only patho-phyisiology of GERD symptoms.5 While 30% to 40% of patients

ith GERD have erosive reflux disease, up to 70% have noacroscopic changes in the gastroesophageal junction (ie, non-

rosive reflux).5 A characteristic of GERD is the relapse ofymptoms in many cases successfully treated with proton pumpnhibitors (PPI).6

CD patients often complain of GERD symptoms.7 Moreover,endoscopic investigation of patients with GERD symptoms hassometimes resulted in the diagnosis of an unexpected CDenteropathy.7 Clinical experience has shown that this observa-ion is more commonly associated with GERD symptoms re-ractory to PPI treatment.8 –10 Cuomo et al10 have suggested that

GERD symptoms are frequent in CD patients and that a gluten-free diet (GFD) reduces the relapse rate of these symptoms.Although the first statement is not shared by others,11 most

uthors agree that treatment with a GFD may prevent theecurrence of upper gastrointestinal symptoms.7,11,12 However,he prevalence of GERD symptoms and the effectiveness ofFD in CD patients still remain to be elucidated. Furthermore,

he pathogenesis of GERD symptoms in CD remains unknown.Our present study had 2 aims: (1) to assess the prevalence of

ERD symptoms in CD patients at the time of diagnosis; and2) to explore the long-term impact of treatment with a GFD onERD symptoms. The present study had a double design, a

ross-sectional analysis of a series of consecutive patients eval-ated at the time of diagnosis, and a prospective, longitudinal,

ong-term assessment of symptoms at different time pointsfter initiation of a GFD.

Materials and MethodsSubjectsPatients and controls. From December 2004 to De-

ember 2005, a series of 151 consecutive adult patients whoere newly diagnosed with CD (117 female and 34 male) at the

Abbreviations used in this paper: CD, celiac disease; CI, confidenceinterval; GERD, gastroesophageal reflux disease; GFD, gluten-free diet;GSRS, Gastrointestinal Symptoms Rating Scale; IgA, a-tTG, immuno-globulin A antitissue transglutaminase antibodies; PPI, proton pumpinhibitor.

© 2011 by the AGA Institute1542-3565/$36.00

doi:10.1016/j.cgh.2010.06.017

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March 2011 CELIAC DISEASE AND GASTROESOPHAGEAL REFLUX 215

Small Bowel Diseases Clinic of the “Dr. Carlos Bonorino Uda-ondo” Gastroenterology Hospital were prospectively enrolled inthe cross-sectional part of the study. At the time of initialdiagnosis, these patients were consuming a regular unrestricteddiet. Patients without biopsy-proven CD or already on a GFD atthe time of the first visit were not included in the assessment.We also excluded patients who declined to or were unable toparticipate in the initial and follow-up evaluations.

The diagnosis of CD was based on clinical, serological,and histological criteria. The official diagnosis of CD re-quired the presence of a characteristic CD enteropathy in theduodenal biopsy and was supported by the concomitantpresence of positive antitissue transglutaminase antibodies,antideamidated gliadin peptide antibodies, or endomysialantibodies as well as histological response to a GFD in caseswith enteropathy but a negative serology. Histological dam-age in the intestinal biopsy was graded according to theMarsh=s modified classification where the most severe dam-age assessed was reported.13 Based on the clinical status ofpatients at the time of diagnosis, they were categorized aspresenting classically symptomatic CD (mainly gastrointes-tinal symptoms), atypical forms (subclinical) of CD (chronicanemia, hypertransaminasemia, autoimmune diseases, etc),or a silent clinical course (asymptomatic or silent CD).13

Patients with silent CD were detected during evaluation offirst degree relatives of index cases.14

After applying the inclusion and exclusion criteria, 133 pa-tients were enrolled in the study at the time of diagnosis.Nineteen other patients were excluded due to different reasons:10 patients lived too far from the site for follow-up visits, 4declined participation, 3 were reluctant to start treatment witha GFD, and 2 had already started treatment at the time of thefirst visit. Among the enrolled patients, 98 patients were cate-gorized as having a classical clinical presentation; 35 were con-sidered as presenting atypical (n � 25) or silent CD (n � 10).

A cohort of 70 healthy adults with matched age and genderand without any known former or current disease was includedand assessed as controls.

Longitudinal long-term study. Fifty-three patients(47 women and 6 men, mean age 38 years) completed thelong-term assessment visits at 3 months, 6 months, 1 year, andbeyond 4 years and were included in the prospective longitudi-nal analysis if data for all time points were available.

MethodsAssessment of GERD symptoms. To evaluate

ERD symptoms, we used a subdimension in the Gastroin-estinal Symptoms Rating Scale (GSRS) that focuses oneartburn and acid regurgitation symptoms and is scored on7-graded Likert scale. The GSRS is a disease-specific instru-ent developed based on reviews of gastrointestinal symp-

oms to evaluate common symptoms of gastrointestinal dis-rders.14 The instrument includes 5 subdimensions, 1 of

which is related to gastroesophageal reflux symptoms. In thecase of GERD, the questionnaire has shown good reliability,discriminates symptom severity, and is useful for evaluatingtreatment outcomes.11,15 The GSRS scores range from 0 to 6or both heartburn and regurgitation, where 0 signifies no

ymptoms at all and 6 represents the highest severity. An

average score of �3 for both items is considered as indicativeof moderate to severe GERD.11

Patients underwent periodical clinical assessments, routinelaboratory tests (hemoglobin and serum albumin concentra-tions are reported here), and measurement of serum concentra-tion of immunoglobulin A antitissue transglutaminase anti-bodies (IgA a-tTG) at each time point. The cutoff value for IgAa-tTG antibodies used for positive results was that provided bythe manufacturer (�20 U/mL).

Assessment of compliance with the gluten-freediet. Compliance with the GFD was assessed at 1-year and4-year visits after diagnosis. Based on previous studies,14,16 com-pliance was determined by a combination of: (1) the assessmentby the treating physician; (2) a meticulous enquiry by an expe-rienced dietitian; and (3) self-report by the patient. A 4-day fooddiary of complete intakes by the patient was also considered.The CD-related serology was used as comparators with otherparameters. Based on all these aspects, the physician in chargecategorized the compliance as: (1) strict adherence (absoluteobservance of the GFD); (2) partial adherence (2–3 lapses ormore frequent lapses per month or once or more per week); and(3) no gluten restriction at all.

Study design, ethics, and statistical analysis. Thetudy was prospectively performed on consecutive patients di-gnosed at 1 institution. This analysis is a part of a largeresearch project to assess the quality of life in CD patients,hich was reported separately.14 Upon diagnosis, all patients

underwent a standardized upper endoscopic procedure whereduodenal biopsies were obtained. Endoscopic characteristics ofthe upper gastrointestinal mucosa were reported. After diagno-sis of CD enteropathy, a written consent was obtained. Patientswho agreed to participate in the prospective protocol under-went a complete clinical evaluation. Serum samples were ob-tained for routine hematological tests and specific serology: atthe time of diagnosis while patients were consuming a regularunrestricted diet and at 3 months, 6 months, 9 months, 1 year,and 4 years after they were started on dietary restriction. TheGSRS questionnaire was administered at the same time points.Expert dieticians evaluated patients’ adherence to the GFD andreinforced the importance of the treatment. The study and theconsent form were approved by the Research and Ethical Com-mittees of the Gastroenterology Hospital.

Data were analyzed using the MedCalc version 9.3.8.0 (Med-Calc Software; Broekstraat, Mariakerke, Belgium). Descriptivestatistics are reported as mean and 95% confidence intervals(95% CI) or median and range according to the data distribu-tion pattern. Two statistical analyses were performed in thestudy. First, we made a cross-sectional assessment of GERDsymptoms in CD patients by clinical characterization at diag-nosis and compared with healthy controls. Comparisons be-tween clinical subgroups and between CD patients and controlswere performed using the Student t test, Mann–Whitney U test,�2, or Fisher exact test as appropriate. Second, we assessed theeffect of GFD on GERD symptom outcomes only in patientswho completed all assessments. Comparisons between baselineand posttreatment outcomes were performed using the Studentpair t test and Wilcoxon=s pair test. In addition, we comparedGERD symptoms in CD patients by their degree of compliancewith a GFD using the analysis of variance or Kruskal–Wallis testas appropriate. Univariate and multivariate linear regression

analyses were performed.

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216 NACHMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 3

Cross-sectional assessments upon diagnosis.Table 1 summarizes the demographic and clinical characteris-tics of the CD patients and healthy controls in the study.Patients and controls were well matched in age and the pre-dominance of females. CD patients had a low mean body massindex and a mean hemoglobin concentration below the normalrange. Baseline endoscopies showed hiatal hernia in 4 CDpatients and Barrett=s disease in 1 case (confirmed by histopa-thology). At enrollment, 6 control subjects were using PPI.

GERD symptoms. Compared with healthy controls,patients had significantly higher GERD symptom scores (P �.001). The proportion of individuals with moderate to severesymptoms (�3 points for the average of heartburn and regur-gitation) was 6-fold higher among CD patients than healthycontrols (P � .01) (Table 1). When patients were categorizedccording to CD presentation at the time of diagnosis, those withlassical clinical manifestations had higher GERD symptom scoresP � .01) and a higher proportion of cases with moderate or severeeflux symptoms (P � .03) compared with patients with atypical/ilent CD. Only a quarter of patients with GERD symptomsere using PPIs at the time of CD diagnosis and a minority of

ases had erosive esophagitis based on the baseline endoscopy.

able 1. Demography, Baseline Clinical Characteristics, andBaseline GERD Symptom Scores of Patients WithCD and Healthy Controls and Vs Classical CD

Characteristics CD patients Healthy controls

Number of subjects(females/males)

133 (114/19) 70 (55/15)

Age mean (range) 38.1 (16–72) 39.5 (19–71)Baseline clinical

categorization, n (%)Classical CD 98Atypical/silent CD 35

Serology: IgA a-tTGNumber of cases with

positive test (%)130 (97.7)

Body mass index, median �SEM, kg/cm2

20.2 � 3.1

Serum albumin, mean �SEM, g %

4.0 � 1.5

Hemoglobin, mean � SEM,g %

11.7 � 2.2

GERD symptom scores,mean (95% CI)

Overall CD patients 1.8 (1.5–2.0) 0.7 (0.5–1.0)a

Classic CD 1.9 (1.6–2.3)Atypical/silent CD 1.2 (0.7–1.7)b

Number of cases withscores �3 (%)

Overall CD patients 40 (30.1) 4 (5.7)c

Classic CD 35 (35.0)Atypical/silent CD 5 (15.2)b

Patients with erosiveesophagitis (%)

5 (3.8)

Patients receiving PPIs (%) 12 (9.0) 6 (8.6)

SEM, standard error of the mean.aP � .01.bP � .03.cP � .0001.

igure 1 depicts the number of CD patients (Figure 1A) and r

ealthy controls (Figure 1B) with different scores at diagnosisnd among patients by clinical presentation at baseline (FiguresC and D). Patients with GERD symptoms clustered among thelassically symptomatic CD patients, while atypical/silent casesesemble distribution in healthy controls.

Longitudinal outcomes. Table 2 shows clinical datat different time points for the study cohort with long-termollow-up. With GFD treatment, CD patients improved theirody mass index and hemoglobin concentration at the 3-monthssessment and remained within normal ranges thereafter. ThegA a-tTG antibody also significantly decreased after initiationf the GFD (P � .04). GERD symptom scores improved at the-month assessment and continued the trend (P � .0001). Theroportion of cases with moderate to severe GERD symptomcores (�3) decreased over the same period (P � .001). Botharameters became similar to those of the healthy subjects atvery time point assessed. At the assessment beyond 4 years,nly 2 patients still had scores �3 (3.7%) and were using PPIs.

We also examined GERD symptoms by the degree of com-liance with the GFD at the 4-year time point. At this point, 28tudy cases were considered strictly compliant with the diet andhe remaining patients were considered as partially compliant.linical parameters were comparable (P � not significant) be-

ween patients who were strictly and partially compliant withhe dietary treatment (Table 3). The strictly compliant patientsad significantly lower serum samples positive for the IgA-tTG test (P � .04). Although the amount of gluten consump-ion varied widely among partially compliant cases, no patientas considered by the expert team as not adherent at all. Thenalysis did not show a significant difference based on compli-nce in terms of GERD symptom scores and proportion ofases with moderate to severe GERD symptoms (Table 3).

DiscussionHeartburn and regurgitation are clinical manifestations

associated with GERD and both are common causes for clinicalconsultations. While a minor proportion of cases have erosiveesophagitis (30% to 40%), a majority of patients have the non-erosive type of GERD.4,5 PPI treatment can relieve GERD symp-oms, but a high relapse rate has been reported when treatments discontinued.6 GERD symptoms are rarely studied in CDatients.8 –10 While some studies have focused on endoscopicvidence of erosive esophagitis,8,10 others have only referred tohe presence of GERD symptoms irrespective of mucosal dam-ge.11,12 In contrast, some investigators have considered the

association between GERD and CD as null or weak.10,11 Inter-stingly, the few studies investigating this association agree thatFD may alleviate GERD symptoms and reduce the risk of

elapse after PPI treatment is discontinued.9 –12 The presenttudy estimated the prevalence of GERD symptoms at the timef CD diagnosis and explored the impact of certain clinicalactors. Furthermore, the systematic, prospective follow-up overlong period revealed the course of GERD symptoms and the

ffect of GFD treatment on these symptoms.In this CD patient sample, 30% of cases complained of

oderate to severe GERD symptoms at the time of CD diag-osis, a rate 6-fold higher than the rate seen in healthy controls

4.7%). Only 1 of the 7 patients with moderate to severe symp-oms had erosive esophagitis. Although this prevalence ofERD symptoms among untreated CD patients is the highest

ate reported so far, it should not be generalized to the overall

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March 2011 CELIAC DISEASE AND GASTROESOPHAGEAL REFLUX 217

CD population because the data here reported were derivedfrom patients attending a malabsorption clinic where classicCD presentation is dominant. As seen in this study, patientswith a classic CD picture had significantly higher GERD scoresand greater prevalence of moderate to severe symptoms com-pared with atypical/silent cases.

The outcome of GERD symptoms after initiation of a GFDtreatment showed a rapid resolution during the first 3 monthsafter diagnosis, and the early benefits persisted thereafter withonly a minimal proportion of patients remaining moderatelysymptomatic beyond 4 years. Despite the evidence supportingeffectiveness of GFD in alleviating GERD symptoms, the symp-tom scores did not differ between patients who strictly com-plied with the diet and those with partial compliance over thelong term. It is likely that patients partially compliant with the

Figure 1. Numbers of individuals with different GERD symptom scoresC) classic CD; (D) atypical/silent CD. Gray bars represent number of s

Table 2. Clinical and Biochemical Data and GERD SymptomMonths, 6 Months, 1 Year, and Beyond 4 Years

Baseline 3

Serology, IgA a-tTGCases with positive tests, n (%) 51 (96.2) 3

Body mass indexMedian � SEM 20.6 � 5.0 2

Serum albuminMean � SEM, g % 4.1 � 2.0

HemoglobinMean � SEM, g % 11.5 � 2.5 1

GERD symptoms scores, mean (95% CI)Overall 1.9 (1.4–2.4) 0.8

Number of patients with GERD scores�3 (%)

Overall 16 (30.1)

NOTE. Body mass index calculated as weight in kilograms divided bySEM, standard error of the mean.aP � .001 vs baseline values.bP � .0001 vs baseline values.

cP � .01 vs baseline values.

GFD had decreasing dietary indiscretions over time, as sug-gested by their clinical improvement of CD, which was compa-rable with patients who were strictly compliant to the GFD.However, the small number of patients with partial compliancedid not allow for further subgroup analyses.

A number of causes for GERD symptoms in CD patients canbe hypothesized. Actual reflux of deleterious gastric contentseems to be the most likely pathophysiological mechanismassociated with these symptoms. In this context, the presence oferosive esophagitis supports the reflux etiology in at least 4% ofall cases. The resolution of GERD symptoms after GFD and thehigher prevalence of nonerosive GERD in this study populationthan previously reported in patients with well-establishedGERD4-6 suggests that some CD patients might have a differentpathophysiological mechanism for GERD symptoms.

e time of CD diagnosis. (A) Overall CD population; (B) healthy controls;ts with scores �3.

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.8)a 30 (56.6)a 32 (60.4)a 21 (39.6)b

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2.5 12.6 � 2.1 12.3 � 1.8 13.4 � 1.7c

–1.1)a 0.7 (0.6–1.3)a 0.8 (0.5–1.1)a 0.6 (0.4–0.8)b

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218 NACHMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 3

Interestingly, it would be reasonable to assume that GERDsymptoms would persist despite CD treatment if they were dueto a true reflux disorder, but the symptom resolution in moststudy patients could mostly be attributable to the implemen-tation of the GFD. Furthermore, we confirm former observa-tions where GERD symptoms do not relapse despite PPIs arediscontinued. Thus, a potential pathogenic role of unknowndisturbances associated with CD could be hypothesised for theGERD symptoms. These mechanisms would explain both thevery low proportion of cases with long-term persistence ofmoderate to severe GERD symptoms, the almost null report ofpatients with symptomatic relapses and a very low rate of PPIuse in the long term. Considering the possibility of alternativeor complementary mechanisms explaining symptoms we ex-plored some interesting aspects of CD. Thus, there is someevidence of reduced upper gastrointestinal motility in patientswith CD.17–19 These few studies have shown abnormal esopha-

eal motility in about 50% of untreated CD cases and discreteotor gastric dysfunction with delayed emptying in almost of

0% of patients.17 Patients on a GFD have shown a trend tonormalization of upper gut motility. Interestingly, a minority ofpatients with esophageal motility disturbances had acid refluxas assessed by pH-metry recording.18 These findings suggesthat upper gastrointestinal motility dysfunction could play aausal role in GERD symptoms; however, this hypothesis re-uires additional research.

Recent data suggest that a permeability defect in the strati-ed esophageal epithelium, producing dilated intercellularpace, is a frequent but nonspecific feature observed in patientsith GERD.20 –22 Although the assertion remains controversial,

it might potentially contribute to the presence of GERD symp-toms. Notably, zonulin, a protein involved in the regulation ofinterepithelial permeability in the intestines of CD patients, wasrecently found to be expressed in the esophageal epithelial cellsas well.23 Although the expression of zonulin was not shown to

e associated with esophageal mucosal damage, a theoreticalole of the protein might account for the occurrence of GERDymptoms in CD patients. Based on these findings, a true linketween active CD and the presence of reflux symptoms cannote ruled out.

In conclusion, our study confirms that moderate to severeERD symptoms are more frequent in patients with undiag-osed CD than in the healthy population. The symptoms rap-

dly resolved in 3 months after the initiation of a GFD and

Table 3. Clinical Parameters and GERD Scores for CD Patienas Strictly Complaint or Partially Compliant With the

Characteristic

umber (F/M)erology, IgA a-tTG, cases with positive tests, n (%)

Body mass index, median � SEMSerum albumin, mean � SEM, g %Hemoglobin, mean � SEM, g %GERD symptom scores, mean (95% CI)Number of patients with scores �3 (%)

NOTE. Body mass index calculated as weight in kilograms divided byF, female; M, male; SEM, standard error of the mean.aP � .04.

mprovement persisted over the long term. Patients with strict

nd partial compliance with the GFD showed no significantifference in GERD symptoms in the long-term follow-up.lthough the pathogenesis of GERD symptoms in CD remainslusive, it is likely multifactorial. The fact that CD treatment isffective against GERD symptoms and relapse suggests thatomponents in the CD pathogenesis may be linked to GERDymptoms.

References

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3. Green PH. The many faces of celiac disease: clinical presentationof celiac disease in the adult population. Gastroenterology 2005;128 (Suppl 1):S74–S78.

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ssessed Beyond 4 Years After Diagnosis and Categorized

Strict compliance Partial compliance

28 (23/5) 25 (24/1)25.0 (7.9–42.1) 51.9 (31.7–72.0)a

24.1 (22.7–25.5) 24.4 (22.7–26.0)4.3 (4.1–4.5) 4.4 (4.2–4.6)

13.4 (12.9–13.8) 13.3 (12.6–14.0)0.5 (0.2–0.9) 0.6 (0.3–0.9)

2 (7.0) 0

square of height in meters.

ts AGFD

the

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1

1

1

1

1

2

March 2011 CELIAC DISEASE AND GASTROESOPHAGEAL REFLUX 219

14. Nachman F, Mauriño E, Vázquez H, et al. Quality of life in celiacdisease patients. Prospective analysis on the importance ofclinical severity at diagnosis and the impact of treatment. Dig LivDis 2009;41:15–25.

5. Revicki DA, Wood M, Wiklund I, et al. Reliability and validity of theGastrointestinal Symptom Rating Scale in patients with gastro-esophageal reflux disease. Qual Life Res 1998;7:75–83.

6. Sugai E, Nachman F, Váquez H, et al. Dynamics of celiac disease-specific serology after initiation of a gluten-free diet and use inthe assessment of compliance with treatment. Dig Liver Dis.2010; 42: 352–8.

7. Usai P, Bassotti G, Usai Satta P, et al. Oesophageal motility inadult coeliac disease. Neurogastroenterol Motil 1995;7:239–244.

8. Bassotti G, Villanacci V, Mazzocchi A, et al. Antroduodenojejunalmotor activity in untreated and treated celiac disease patients. JGastroenterol Hepatol 2008;23:e23–e28.

9. Usai P, Usai Satta P, Lai M, et al. Autonomic dysfunction andupper digestive functional disorders in untreated adult coeliacdisease. Eur J Clin Invest 1997;27:1009–1015.

0. Van Malenstein H, Farré R, Sifrim D. Esophageal dilated intercel-lular spaces (DIS) and nonerosive reflux disease. Am J Gastro-

enterol. 2008;103:1021–1028.

21. Söderholm JD. Stress-related changes in oesophageal permea-bility: filling the gaps of GORD? Gut 2007;56:1177–1180.

22. Farré R, van Malenstein H, De Vos R, et al. Short exposure ofoesophageal mucosa to bile acids, both in acidic and weaklyacidic conditions, can impair mucosal integrity and provoke di-lated intercellular spaces. Gut 2008;57:1366–1374.

23. Wex T, Mönkemüller K, Kuester D, et al. Zonulin is not increasedin the cardiac and esophageal mucosa of patients with gastro-esophageal reflux disease. Peptides 2009;30:1082–1087.

Reprint requestsAddress requests for reprints to: Prof Julio C. Bai, MD, Department

of Medicine, Dr C. Bonorino Udaondo Gastroenterology Hospital, Ave-nue Caseros 2061, (1264) Buenos Aires, Argentina. e-mail: jbai@intramed.net; fax: (5411) 4304-1018.

Conflicts of interestThe authors disclose no conflicts.

FundingThe study was supported in part by the Consejo de Investigaciones

en Salud (CIS), Ministerio de Salud, Gobierno de la Ciudad de Buenos

Aires.