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Information sources and cancer risk in subjects with Barrett’s esophagus
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688 INFORMATION SOURCES AND CANCER RISK IN SUBJECTS WITH BARRETT’S ESOPHAGUS Bryan Green, M.D., Nicholas J. Shaheen, M.D., Marc Noble, M.D., Sarah M. Schmitz, B.A., Jeffrey T. Wei, M.D., Dawn Provenzale, M.D., FACG*. Duke University Medical Center, Durham, NC; University of North Carolina, Chapel Hill, NC and Durham VA Medical Center, Durham, NC. Purpose: There is uncertainty about cancer risk in patients with Barrett’s esophagus (BE), and there are few data on patients’ perception of cancer risk. The purposes of this study were to: 1) examine sources of patient information about BE in two distinct populations (VA and non-VA) and; 2) to compare perceived cancer risk among the groups. Methods: Subjects with documented Barrett’s esophagus were enrolled at the Durham VAMC (VA) and the University of North Carolina (non-VA). Patients completed a cancer risk assessment questionnaire, which also examined sources of information regarding BE. Univariate and bivariate analyses were conducted to compare demographic data, symptom severity, sources of information, and perceived cancer risk among the groups. A logistic regression model was created to examine perceived cancer risk by site, controlling for education, gender, age and symptom severity. Results: Seventy-two patients were enrolled (26, VA). The mean age was 60, 82% were male, 94% were white. VA patients were slightly older (57 vs. 63 years, p0.02). The non-VA group contained more women (13 vs. 0, p0.001). On a scale of 0 to 5 (0 no symptoms, 5 highly symptomatic) the VA group rated their symptoms as significantly worse than the non-VA group (3.9 vs. 3.2, p0.045). Seventy-eight percent of patients identified their physician as the primary source of information about BE. While 34% stated that they obtained information from the internet, only 14% thought it was more useful than their physician. There was no difference among the groups in information sources. Patients who got information from the Internet were no more likely to over-estimate their cancer risk than those who got information from their doctor alone. Vet- erans perceived a 22% risk of getting cancer in the upcoming year, vs. 8% in the non-veterans (p0.001). The VA group thought that their lifetime cancer risk was 30% vs. 17% in the non-VA group (p0.051). These differences in perceived cancer risk persisted after adjusting for age, gender, race, and symptom severity in a logistic regression model. Conclusions: 1) The physician was the primary data source for both groups. 2) VA patients had a higher perceived cancer risk than non-VA patients, although both greatly over-estimated their risk of cancer. 3) VA patients had more severe reflux than non-VA patients, which was associ- ated with a greater perceived cancer risk. 4) Interventions to educate BE patients about cancer risk are needed. 689 GLIADIN INDUCES A ZONULIN-DEPENDENT INCREASED INTESTINAL PERMEABILITY AND DECREASED EXPRESSION OF TIGHT JUNCTION PROTEINS IN AN EX- VIVO HUMAN INTESTINAL MODEL OF CELIAC DISEASE Sandro Drago, Ramzi El Asmar, Cinzia D’Agate, Giuseppe Iacono, Mariarosaria Di Pierro, Carlo Catassi, M.D., Alessio Fasano, M.D.*. University of Maryland School of Medicine, Baltimore, MD; University of Ancona, Ancona, Italy; University of Catania, Catania, Italy and University of Palermo, Palermo, Italy. Purpose: Despite the progress made in understanding the immunological aspects of celiac disease (CD) pathogenesis, the early steps that allow gliadin to cross the intestinal barrier are still largely unknown. To inves- tigate the effect of gliadin on the intestinal barrier function using duodenal biopsies obtained from CD patients in remission. Methods: Intestinal biopsies obtained from CD patients in remission were mounted in the polarized microsnapwell system and exposed at increasing time intervals to gliadin added to the luminal (mucosal) side of the tissue. Transepithelial electrical resistance (TEER) was measured in the micros- napwell assay, release of zonulin, a modulator of intracellular tight junc- tions (TJ), measured by sandwich-ELISA, and occluding mRNA expres- sion evaluated using PCR Real Time with the TaqMan probes technique. Results: Duodenal tissues exposed to gliadin showed a greater decrement in TEER ( TEER, mean SE: 73.0 9.1 cm 2 ;n12) compared to tissue exposed of bovine serum albumin control (150 10.9; n7). The gliadin-induced TEER decrease was mirrored by zonulin release into the apical (1.06 0.27 ng/mg protein; controls 0.11 0.039) but not baso- lateral (0.17 0.012) intestinal media. Tissues pretreatment with the zonu- lin inhibitor FZI/O partially prevented TEER decrement (39.8 10.1) without affecting mucosal zonulin release (0.92 0.19). Intestinal tissues exposed to gliadin showed also a decrease in mRNA occludin (120,000 copies/10 6 copies GAPDH). These changes were also observed in CD patients during the acute phase of the disease (150,000 copies/10 6 copies GAPDH for occludin, 130,000 for ZO-1) and reverted following a gluten free diet. Conclusions: Intestinal mucosa of CD patients in remission luminally exposed to gliadin showed a zonulin-dependent drop in TEER, paralleled by a decrease in occluding expression. These results suggest that gliadin may play a pivotal role in facilitating its own passage to the submucosal compartment were triggers the immune-mediated procedded typical of the disease in genetically susceptible individuals. 690 ZONULIN, AN INTESTINAL TIGHT JUNCTION MODULATOR, IS INVOLVED IN THE PATHOGENESIS OF TYPE I DIABETES Anna Sapone, M.D., Laura de Magistris, Dario Iafusco, M.D., Franco Prisco, M.D., Romano Carratu’, M.D., Barbara Bizzarri, M.D., Maria Grazia Clemente, M.D., Maria Paola Musu, Rosanna Lampis, Francesco Cucca, Gavina Piredda, M.D., Debra Counts, M.D., Alessio Fasano, M.D.*. University of Maryland School of Medicine, Baltimore, MD; Seconda Universita’ degli Studi di Napoli, Napoli, Italy and Universita’ degli Studi di Cagliari, Cagliari, Italy. Purpose: We have previously showed that zonulin-dependent increase in intestinal permeability precedes the autoimmune process in the BB/Wor animal model of type 1 diabetes. Aims of our study were to verify the association between serum zonulin level and in vivo intestinal permeability in patients with type1 diabetes and their relatives and to investigate zonulin serum level in different stages of the autoimmune process. Methods: In vivo intestinal permeability was performed by using the Lactulose/Mannitol (LA/MA) double sugar test. The presence of the sugar probes in a 5h urine collection sample was determined by HPLC and permeability assed by their ratio. The zonulin serum level was determined by a sandwich ELISA. Both in vivo intestinal permeability and zonulin measurement were performed in a total of 16 type 1 diabetes subjects and 27 first degree relatives. Serum zonulin levels were also obtained in four groups of subjects: 8 subjects with established type1 diabetes, 4 subjects with type 1 diabetes whose serum was obtained before the onset of the disease, 6 subjects with only elevated auto-antibodies (potential type 1 diabetes) and, 15 healthy relatives. Results: Type 1 diabetes patients showed both increased LA/MA ratio (p0.01) and serum zonulin levels (p 0,00001) compared to controls, 10of 16 (62%) type1 diabetic patients showed LA/MA ratio above 2 standard deviation cutoff compared to 7 out of 27 (26%) first-degree relatives (p0.01). Subjects with zonulin levels above the cutoff showed an overall 75% concordance (6 out of 8 in IDDM patients and 3 out of 4 in relatives) with abnormal LA/MA ratio. Zonulin tested above the cutoff in 8 out of 16 (50%) type 1 diabetes patients and 3 out of 27 (11%) in non-diabetic first-degree relatives (p0.01 by two tail Fisher’s exact test). Zonulin was also elevated in 75% of the subjects whose blood was drawn before the onset of the disease and 66% of non-diabetic patients with elevated auto-antibodies (potential diabetes). Conclusions: These results support the hypothesis that zonulin, as a marker of increased intestinal permeability, precedes the development of the au- toimmune response that causes destruction of islet cells leading to diabetes in subjects who are known to develop auto-antibodies (sero-converters). S228 Abstracts AJG – Vol. 98, No. 9, Suppl., 2003
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Transcript of Information sources and cancer risk in subjects with Barrett’s esophagus
688
INFORMATION SOURCES AND CANCER RISK IN SUBJECTSWITH BARRETT’S ESOPHAGUSBryan Green, M.D., Nicholas J. Shaheen, M.D., Marc Noble, M.D.,Sarah M. Schmitz, B.A., Jeffrey T. Wei, M.D.,Dawn Provenzale, M.D., FACG*. Duke University Medical Center,Durham, NC; University of North Carolina, Chapel Hill, NC andDurham VA Medical Center, Durham, NC.
Purpose: There is uncertainty about cancer risk in patients with Barrett’sesophagus (BE), and there are few data on patients’ perception of cancerrisk. The purposes of this study were to: 1) examine sources of patientinformation about BE in two distinct populations (VA and non-VA) and; 2)to compare perceived cancer risk among the groups.Methods: Subjects with documented Barrett’s esophagus were enrolled atthe Durham VAMC (VA) and the University of North Carolina (non-VA).Patients completed a cancer risk assessment questionnaire, which alsoexamined sources of information regarding BE. Univariate and bivariateanalyses were conducted to compare demographic data, symptom severity,sources of information, and perceived cancer risk among the groups. Alogistic regression model was created to examine perceived cancer risk bysite, controlling for education, gender, age and symptom severity.Results: Seventy-two patients were enrolled (26, VA). The mean age was60, 82% were male, 94% were white. VA patients were slightly older (57vs. 63 years, p�0.02). The non-VA group contained more women (13 vs.0, p�0.001). On a scale of 0 to 5 (0 � no symptoms, 5 � highlysymptomatic) the VA group rated their symptoms as significantly worsethan the non-VA group (3.9 vs. 3.2, p�0.045). Seventy-eight percent ofpatients identified their physician as the primary source of informationabout BE. While 34% stated that they obtained information from theinternet, only 14% thought it was more useful than their physician. Therewas no difference among the groups in information sources. Patients whogot information from the Internet were no more likely to over-estimate theircancer risk than those who got information from their doctor alone. Vet-erans perceived a 22% risk of getting cancer in the upcoming year, vs. 8%in the non-veterans (p�0.001). The VA group thought that their lifetimecancer risk was 30% vs. 17% in the non-VA group (p�0.051). Thesedifferences in perceived cancer risk persisted after adjusting for age,gender, race, and symptom severity in a logistic regression model.Conclusions: 1) The physician was the primary data source for bothgroups. 2) VA patients had a higher perceived cancer risk than non-VApatients, although both greatly over-estimated their risk of cancer. 3) VApatients had more severe reflux than non-VA patients, which was associ-ated with a greater perceived cancer risk. 4) Interventions to educate BEpatients about cancer risk are needed.
689
GLIADIN INDUCES A ZONULIN-DEPENDENT INCREASEDINTESTINAL PERMEABILITY AND DECREASEDEXPRESSION OF TIGHT JUNCTION PROTEINS IN AN EX-VIVO HUMAN INTESTINAL MODEL OF CELIAC DISEASESandro Drago, Ramzi El Asmar, Cinzia D’Agate, Giuseppe Iacono,Mariarosaria Di Pierro, Carlo Catassi, M.D., Alessio Fasano, M.D.*.University of Maryland School of Medicine, Baltimore, MD; Universityof Ancona, Ancona, Italy; University of Catania, Catania, Italy andUniversity of Palermo, Palermo, Italy.
Purpose: Despite the progress made in understanding the immunologicalaspects of celiac disease (CD) pathogenesis, the early steps that allowgliadin to cross the intestinal barrier are still largely unknown. To inves-tigate the effect of gliadin on the intestinal barrier function using duodenalbiopsies obtained from CD patients in remission.Methods: Intestinal biopsies obtained from CD patients in remission weremounted in the polarized microsnapwell system and exposed at increasingtime intervals to gliadin added to the luminal (mucosal) side of the tissue.Transepithelial electrical resistance (TEER) was measured in the micros-
napwell assay, release of zonulin, a modulator of intracellular tight junc-tions (TJ), measured by sandwich-ELISA, and occluding mRNA expres-sion evaluated using PCR Real Time with the TaqMan probes technique.Results: Duodenal tissues exposed to gliadin showed a greater decrementin TEER (� TEER, mean � SE: �73.0 � 9.1 cm2; n�12) compared totissue exposed of bovine serum albumin control (�150 � 10.9; n�7). Thegliadin-induced TEER decrease was mirrored by zonulin release into theapical (1.06 � 0.27 ng/mg protein; controls 0.11 � 0.039) but not baso-lateral (0.17 �0.012) intestinal media. Tissues pretreatment with the zonu-lin inhibitor FZI/O partially prevented TEER decrement (�39.8 � 10.1)without affecting mucosal zonulin release (0.92 � 0.19). Intestinal tissuesexposed to gliadin showed also a decrease in mRNA occludin (�120,000copies/106 copies GAPDH). These changes were also observed in CDpatients during the acute phase of the disease (�150,000 copies/106 copiesGAPDH for occludin, �130,000 for ZO-1) and reverted following a glutenfree diet.Conclusions: Intestinal mucosa of CD patients in remission luminallyexposed to gliadin showed a zonulin-dependent drop in TEER, paralleledby a decrease in occluding expression. These results suggest that gliadinmay play a pivotal role in facilitating its own passage to the submucosalcompartment were triggers the immune-mediated procedded typical of thedisease in genetically susceptible individuals.
690
ZONULIN, AN INTESTINAL TIGHT JUNCTION MODULATOR,IS INVOLVED IN THE PATHOGENESIS OF TYPE I DIABETESAnna Sapone, M.D., Laura de Magistris, Dario Iafusco, M.D.,Franco Prisco, M.D., Romano Carratu’, M.D., Barbara Bizzarri, M.D.,Maria Grazia Clemente, M.D., Maria Paola Musu, Rosanna Lampis,Francesco Cucca, Gavina Piredda, M.D., Debra Counts, M.D.,Alessio Fasano, M.D.*. University of Maryland School of Medicine,Baltimore, MD; Seconda Universita’ degli Studi di Napoli, Napoli, Italyand Universita’ degli Studi di Cagliari, Cagliari, Italy.
Purpose: We have previously showed that zonulin-dependent increase inintestinal permeability precedes the autoimmune process in the BB/Woranimal model of type 1 diabetes. Aims of our study were to verify theassociation between serum zonulin level and in vivo intestinal permeabilityin patients with type1 diabetes and their relatives and to investigate zonulinserum level in different stages of the autoimmune process.Methods: In vivo intestinal permeability was performed by using theLactulose/Mannitol (LA/MA) double sugar test. The presence of the sugarprobes in a 5h urine collection sample was determined by HPLC andpermeability assed by their ratio. The zonulin serum level was determinedby a sandwich ELISA. Both in vivo intestinal permeability and zonulinmeasurement were performed in a total of 16 type 1 diabetes subjects and27 first degree relatives. Serum zonulin levels were also obtained in fourgroups of subjects: 8 subjects with established type1 diabetes, 4 subjectswith type 1 diabetes whose serum was obtained before the onset of thedisease, 6 subjects with only elevated auto-antibodies (potential type 1diabetes) and, 15 healthy relatives.Results: Type 1 diabetes patients showed both increased LA/MA ratio(p�0.01) and serum zonulin levels (p� 0,00001) compared to controls,10of 16 (62%) type1 diabetic patients showed LA/MA ratio above 2standard deviation cutoff compared to 7 out of 27 (26%) first-degreerelatives (p�0.01). Subjects with zonulin levels above the cutoff showed anoverall 75% concordance (6 out of 8 in IDDM patients and 3 out of 4 inrelatives) with abnormal LA/MA ratio. Zonulin tested above the cutoff in8 out of 16 (50%) type 1 diabetes patients and 3 out of 27 (11%) innon-diabetic first-degree relatives (p�0.01 by two tail Fisher’s exact test).Zonulin was also elevated in 75% of the subjects whose blood was drawnbefore the onset of the disease and 66% of non-diabetic patients withelevated auto-antibodies (potential diabetes).Conclusions: These results support the hypothesis that zonulin, as a markerof increased intestinal permeability, precedes the development of the au-toimmune response that causes destruction of islet cells leading to diabetesin subjects who are known to develop auto-antibodies (sero-converters).
S228 Abstracts AJG – Vol. 98, No. 9, Suppl., 2003
