t2079 reduced 5-hydroxytryptamine (5-ht) signaling determines stool consistency and transit in...

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The present findings show a significant association of LS/SS 5HTTLPR genotypes with symptom severity in patients with D-IBS and C-IBS. This observation suggests a pathogenic relationship between genetic variations of SERT and gut hypersensitivity in IBS, which could translates into different levels of symptom severity in the clinical setting. Table 1 T2076 Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome is Significantly Associated With Increased Contractility of the Rectum in Response to Balloon Distension Viola Andresen, Jutta Keller, Henning Hohendorf, Aleksandr Sumenko, Michael Schemann, Peter H. Layer Background: Visceral hypersensitivity (VH) is considered a pivotal pathogenic factor in the irritable bowel syndrome (IBS). VH is believed to reflect increased conscious perception of gut stimuli and may be assessed by reduced pain thresholds (32 mmHg; [1]) during rectal balloon distension. On the other hand, in some patients, rectal balloon distension may also induce contractile responses. Whether the occurrence of contractions is associated with reduced pain thresholds has not been investigated. Aim: To investigate in IBS patients whether VH is associated with increased contractile responses to rectal balloon distension. Methods: 84 consecutive IBS patients underwent a series of rectal isobaric balloon distension tests with stepwise pressure increase from 0 to 48 mmHg using an electronic barostat. Pain thresholds were assessed by recording the patients' rectal sensations (ranging from 0=”no sensation” to 7=”pain”) in response to each distension. An investigator blinded to the pain thresholds visually analyzed the occurrence of marked contractions of the rectum wall determined by volume depressions in the pressure-volume curves. Statistics included ChiSq- uare- and T-tests. Results: Overall, 38% (n=32) of patients had VH with rectal pain thresholds 32 mm Hg. The proportion of patients producing distension-induced contractions was 27% (n= 23) of the entire cohort. There was a highly significant association between the occurrence of contractions and the presence of VH: 15% of patients with normal pain thresholds had contractions compared to 47% of hypersensitive patients (p<0.002). Con- versely, 65% of patients with contractions had VH (p<0.002). Moreover, rectal pain thresholds were significantly lower in patients with contractions compared to those without (31.8±8.8 vs. 38.1±9.3 mm Hg; p<0.007). Conclusion: In this population of IBS patients, VH determined by reduced rectal pain thresholds was significantly associated with the occurrence of increased rectal contractility in response to balloon distension. These findings suggest 1) increased motor reflex responses as component of VH; and/or 2) an important contribution of these contractions to visceral pain generation. Indeed, recent observations indicate deformation- increased activity of mechanosensitive neurons even at constant wall tension [2]. Hence, contractile intestinal wall deformations following distension might per se increase pain perception in a subgroup of patients. These findings could have potential future diagnostic and therapeutic implications. 1. Bouin et al. Gastroenterology 2002;122:1771-1777 2. Maz- zuoli & Schemann. J Physiol 2009;587:4681-94 T2077 Functional Dyspepsia (FD) and Irritable Bowel Syndrome (IBS), Any Similarity at Cytokine Level? Salah E. Ahmed, Shane P. Duggan, Dermot P. Kelleher, Nasir Mahmud, Timothy G. Dinan, Dermot O'Toole, Napolean Keeling Background & Aim: Functional dyspepsia (FD) and irritable bowel syndrome (IBS) display overlapping symptoms in up to 50% of patients. Furthermore, both conditions show epidemi- ological and pathophysiological similarities. Inflammatory markers are useful tools in the staging and isotyping of many diseases. Traditional ELISA based techniques for cytokine profiling have been demonstrated to lack in sensitivity in determining levels in control patients and in observing subtle alterations in cytokine levels in functional GI disorder. Therefore, we aimed to utilize a new highly sensitive method to examine cytokine profiles in FD and IBS cohorts and to determine potential molecular similarities between the two conditions. Methods: Patient cohorts of FD (n=25), diarrhoea predominant IBS (n=20) and age and gender matched healthy control (n=17) were enrolled in this study (male=22, female= 40; median age 34 yrs). Rome III criteria were met for all FD and IBS. Plasma cytokine expression was measured using the highly sensitive Mesoscale discovery (MSD) platform:- IFN-G, IL10, IL12P70, IL2, 1L6, 1L8, and TNFA. Data was analyzed by using Mann-Whitney test with SPSS software. Results: Significant differences were observed in IL10 and IL12p70 levels between FD and control patients with no differences observed between IBS and control cohort. Mean ranked values for IL10 were 8.7 pg/ml in FD patients by comparison to control levels of 6.5 pg/ml (p<0.023 Mann Whitney). IL12p70 levels opposed that observed for IL10 with lower mean ranked levels observed in FD patients (4.7 pg/ml) compared to controls (49 pg/ml; p<0.004). However, mean levels of IL10 and IL12p70 were not significantly different in IBS patients compared to controls. Additionally, levels of TNF were significantly altered in IBS patients (3.84pg/ml) with respect to controls (1.06pg/ ml p<0.013) but not in FD patients. There were no statistically significant changes observed for the other cytokine tested between both groups compared to controls. Conclusion: This study detailed significant alterations in anti-inflammatory cytokines in FD. These alterations were not observed in IBS groups indicating dissimilarity between both groups at a molecular level. This study utilized a highly sensitive assay to determine basal levels of these cytokines and succeeded in demonstrating significant alterations at levels previously undetectable by S-627 AGA Abstracts conventional methodologies. The variation at the cytokine level may support the hypothesis that FD and IBS are not a single disease. More studies are needed for further evaluate the contribution of the observed cytokines alterations to these diseases. T2078 Prevalence of Irritable Bowel Syndrome in First-Degree Relatives of Patients With Inflammatory Bowel Disease. Quality of Life and Economic Impact Mariam Aguas, Vicente Garrigues, Guillermo Bastida, Pilar Nos, Vicente Ortiz, Julio Ponce BACKGROUND: Epidemiological studies have shown a greater prevalence of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), and negative impact of quality of life (QoL), among first-degree relatives of patients diagnosed of these diseases. However, it is not known IBS prevalence and QoL in first-degree relatives of patients with IBD. OBJECT- IVE: To analyse IBS prevalence among first-degree relatives of patients diagnosed with Crohn's disease or ulcerative colitis, and to assess the QoL and use of healthcare resources. MATERIALS AND METHODS: A prevalence study was conducted including 490 relatives of 108 patients with IBD. The following demographic information was collected: age, sex, cohabitation and kinship with the index case: consanguinity (parents, siblings, offspring) or affinity (spouses). QoL was assessed using a generic questionnaire, the Short Form-36 Health Survey. IBS was defined according to Rome I and Rome II criteria and the use of healthcare resources was evaluated with medical consultations and self-prescribed drugs for their bowel symptoms in the past year. RESULTS: The overall prevalence of IBS among the first-degree relatives of patients with IBD (n=360) was 49.4% according to Rome I criteria and 10% according to Rome II criteria, porcentages much higher than those established for the general Spanish population: 12.1% and 3.3% respectively. IBS prevalence was higher in first-degree blood relatives than in spouses (Rome I: 53.1% vs 29.1%, p=0.001; Rome II: 10.8% vs 5.4%, NS). No differences were found in IBS prevalence depending on cohabita- tion with the index case. Of all relatives meeting the Rome I and Rome II criteria, 40.4% and 69.4% respectively had consulted for bowel symptoms in the past year, and many of those who had not consulted had self-medicated (Rome I: 22.6%; Rome II: 54.5%). Relatives who met Rome I and Rome II criteria showed worse QoL than general Spanish population. Patients with IBD had similar QoL than relatives who met Rome II criteria, but worse than relatives who met Rome I criteria. The QoL worsening was associated with increased consumption of health resources (medical consultations and self-prescribed drugs) in relatives of patients with IBD. CONCLUSIONS: IBS prevalence in first-degree relatives of patients diagnosed with IBD is significantly elevated. It is significantly greater in first-degree blood relatives, which suggests the implication of genetic rather than psychological-environmental factors. Relatives of patients with IBD who meet the Rome I and Rome II criteria show worse QoL and use more healthcare resources for bowel symptoms than relatives who do not meet IBS criteria. T2079 Reduced 5-Hydroxytryptamine (5-HT) Signaling Determines Stool Consistency and Transit in Functional GI Patients With Constipation Chander Shekhar, Phillip J. Monaghan, Basma Issa, Peter J. Whorwell, Brian Keevil, Julie Morris, Lesley A. Houghton Studies have shown that platelet depleted plasma (PDP) 5-HT concentration increases with meal ingestion (1,2) and that this change (fasting to fed) is significantly reduced in IBS-C patients compared with controls (2,3). Furthermore, low levels of postprandial 5-HT (not referenced to fasting) tend (p=.09) to associate with prolonged colonic transit, but only when a mixed group of post-infective and IBS-C patients were assessed together (3). Our aim was to explore this further, by assessing pre- and post-prandial PDP 5-HT concentrations, orocecal and colonic transit, and stool consistency in functional GI patients with constipation. Methods: 15 female patients (13 IBS-C and 2 functional constipation, aged 21-53yrs) and 8 healthy females (aged 21-44 yrs) were recruited. Following a 7 day diary in which stool consistency (Bristol Stool Scale, BSS) was assessed, PDP 5-HT concentration was measured under both fasting (2hrs) and fed (4hrs) conditions. Within 2 weeks, orocecal (hydrogen breath test) and colonic (radio-opaque markers for 3 days followed by X-ray) transit were determined. 5-HT concentration was assessed using rapid liquid chromatography tandem mass spectrometry (4). Results: Patients had significantly reduced 5-HT responses to meal ingestion (mean increase from fasting (SD): + 0.96nmol/L(±5.81) v + 6.93nmol/L(±4.78); p=.02), delayed colonic (59.67hrs (±10.88) v 36.88hrs(±15.84); p=.001) but not orocecal (328.87min(±94.27) v 325.75min(±94.54); p=.941) transit, and harder stools (BSS: 2.34(±1.17) v 3.8(±1.09); p=.008) compared with controls. Sub-grouping patients into those with severe (BSS 2) and mild (BSS>2) constipation, showed that those with severe constipation had significantly reduced 5-HT responses to meal ingestion (-0.57nmol/ L(±6.51); p=.04) and slower colonic (61.57hrs(±9.79): p=.004) but not orocecal (298.57min(±37.05); p=1.0) transit compared with controls. However, although patients with mild constipation had slower colonic transit (58.0hrs(±12.16); p=.01), their orocecal transit (355.38min(±121.97); p=1.0) and 5-HT responses to meal ingestion (2.29nmo/ L(±5.17); p=.32) were no different from controls. Interestingly, postprandial PDP 5-HT levels (not referenced to fasting) were no different between severe/mild constipated patients and controls. Conclusions: In patients with constipation, the severity of their constipation is related to their 5-HT response to meal ingestion. The 5-HT response to meal ingestion is a better marker of constipation than actual postprandial 5-HT levels. Refs: (1) Gut 2003;52:663; (2) Gastroenterol 2006;130:34; (3) Clin Gastroenterol Hepatol 2005;3:349; (4) J Chromatogr B 2009;877:2163 AGA Abstracts

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Page 1: T2079 Reduced 5-Hydroxytryptamine (5-HT) Signaling Determines Stool Consistency and Transit in Functional GI Patients With Constipation

The present findings show a significant association of LS/SS 5HTTLPR genotypes withsymptom severity in patients with D-IBS and C-IBS. This observation suggests a pathogenicrelationship between genetic variations of SERT and gut hypersensitivity in IBS, which couldtranslates into different levels of symptom severity in the clinical setting.Table 1

T2076

Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome isSignificantly Associated With Increased Contractility of the Rectum inResponse to Balloon DistensionViola Andresen, Jutta Keller, Henning Hohendorf, Aleksandr Sumenko, MichaelSchemann, Peter H. Layer

Background: Visceral hypersensitivity (VH) is considered a pivotal pathogenic factor in theirritable bowel syndrome (IBS). VH is believed to reflect increased conscious perception ofgut stimuli and may be assessed by reduced pain thresholds (≤ 32 mmHg; [1]) duringrectal balloon distension. On the other hand, in some patients, rectal balloon distensionmay also induce contractile responses. Whether the occurrence of contractions is associatedwith reduced pain thresholds has not been investigated. Aim: To investigate in IBS patientswhether VH is associated with increased contractile responses to rectal balloon distension.Methods: 84 consecutive IBS patients underwent a series of rectal isobaric balloon distensiontests with stepwise pressure increase from 0 to 48 mmHg using an electronic barostat. Painthresholds were assessed by recording the patients' rectal sensations (ranging from 0=”nosensation” to 7=”pain”) in response to each distension. An investigator blinded to the painthresholds visually analyzed the occurrence of marked contractions of the rectum walldetermined by volume depressions in the pressure-volume curves. Statistics included ChiSq-uare- and T-tests. Results: Overall, 38% (n=32) of patients had VHwith rectal pain thresholds≤32 mm Hg. The proportion of patients producing distension-induced contractions was27% (n= 23) of the entire cohort. There was a highly significant association between theoccurrence of contractions and the presence of VH: 15% of patients with normal painthresholds had contractions compared to 47% of hypersensitive patients (p<0.002). Con-versely, 65%of patients with contractions had VH (p<0.002). Moreover, rectal pain thresholdswere significantly lower in patients with contractions compared to those without (31.8±8.8vs. 38.1±9.3mmHg; p<0.007). Conclusion: In this population of IBS patients, VHdeterminedby reduced rectal pain thresholds was significantly associated with the occurrence of increasedrectal contractility in response to balloon distension. These findings suggest 1) increasedmotor reflex responses as component of VH; and/or 2) an important contribution of thesecontractions to visceral pain generation. Indeed, recent observations indicate deformation-increased activity of mechanosensitive neurons even at constant wall tension [2]. Hence,contractile intestinal wall deformations following distension might per se increase painperception in a subgroup of patients. These findings could have potential future diagnosticand therapeutic implications. 1. Bouin et al. Gastroenterology 2002;122:1771-1777 2. Maz-zuoli & Schemann. J Physiol 2009;587:4681-94

T2077

Functional Dyspepsia (FD) and Irritable Bowel Syndrome (IBS), AnySimilarity at Cytokine Level?Salah E. Ahmed, Shane P. Duggan, Dermot P. Kelleher, Nasir Mahmud, Timothy G.Dinan, Dermot O'Toole, Napolean Keeling

Background & Aim: Functional dyspepsia (FD) and irritable bowel syndrome (IBS) displayoverlapping symptoms in up to 50% of patients. Furthermore, both conditions show epidemi-ological and pathophysiological similarities. Inflammatory markers are useful tools in thestaging and isotyping of many diseases. Traditional ELISA based techniques for cytokineprofiling have been demonstrated to lack in sensitivity in determining levels in controlpatients and in observing subtle alterations in cytokine levels in functional GI disorder.Therefore, we aimed to utilize a new highly sensitive method to examine cytokine profilesin FD and IBS cohorts and to determine potential molecular similarities between the twoconditions. Methods: Patient cohorts of FD (n=25), diarrhoea predominant IBS (n=20) andage and gender matched healthy control (n=17) were enrolled in this study (male=22,female= 40; median age 34 yrs). Rome III criteria were met for all FD and IBS. Plasmacytokine expression was measured using the highly sensitive Mesoscale discovery (MSD)platform:- IFN-G, IL10, IL12P70, IL2, 1L6, 1L8, and TNFA. Data was analyzed by usingMann-Whitney test with SPSS software. Results: Significant differences were observed inIL10 and IL12p70 levels between FD and control patients with no differences observedbetween IBS and control cohort. Mean ranked values for IL10 were 8.7 pg/ml in FD patientsby comparison to control levels of 6.5 pg/ml (p<0.023 Mann Whitney). IL12p70 levelsopposed that observed for IL10 with lower mean ranked levels observed in FD patients (4.7pg/ml) compared to controls (49 pg/ml; p<0.004). However, mean levels of IL10 and IL12p70were not significantly different in IBS patients compared to controls. Additionally, levels ofTNF were significantly altered in IBS patients (3.84pg/ml) with respect to controls (1.06pg/ml p<0.013) but not in FD patients. There were no statistically significant changes observedfor the other cytokine tested between both groups compared to controls. Conclusion: Thisstudy detailed significant alterations in anti-inflammatory cytokines in FD. These alterationswere not observed in IBS groups indicating dissimilarity between both groups at a molecularlevel. This study utilized a highly sensitive assay to determine basal levels of these cytokinesand succeeded in demonstrating significant alterations at levels previously undetectable by

S-627 AGA Abstracts

conventional methodologies. The variation at the cytokine level may support the hypothesisthat FD and IBS are not a single disease. More studies are needed for further evaluate thecontribution of the observed cytokines alterations to these diseases.

T2078

Prevalence of Irritable Bowel Syndrome in First-Degree Relatives of PatientsWith Inflammatory Bowel Disease. Quality of Life and Economic ImpactMariam Aguas, Vicente Garrigues, Guillermo Bastida, Pilar Nos, Vicente Ortiz, JulioPonce

BACKGROUND: Epidemiological studies have shown a greater prevalence of irritable bowelsyndrome (IBS) and inflammatory bowel disease (IBD), and negative impact of quality oflife (QoL), among first-degree relatives of patients diagnosed of these diseases. However, itis not known IBS prevalence and QoL in first-degree relatives of patients with IBD. OBJECT-IVE: To analyse IBS prevalence among first-degree relatives of patients diagnosed withCrohn's disease or ulcerative colitis, and to assess the QoL and use of healthcare resources.MATERIALS AND METHODS: A prevalence study was conducted including 490 relativesof 108 patients with IBD. The following demographic information was collected: age, sex,cohabitation and kinship with the index case: consanguinity (parents, siblings, offspring)or affinity (spouses). QoL was assessed using a generic questionnaire, the Short Form-36Health Survey. IBS was defined according to Rome I and Rome II criteria and the use ofhealthcare resources was evaluated with medical consultations and self-prescribed drugs fortheir bowel symptoms in the past year. RESULTS: The overall prevalence of IBS among thefirst-degree relatives of patients with IBD (n=360) was 49.4% according to Rome I criteriaand 10% according to Rome II criteria, porcentages much higher than those established forthe general Spanish population: 12.1% and 3.3% respectively. IBS prevalence was higherin first-degree blood relatives than in spouses (Rome I: 53.1% vs 29.1%, p=0.001; RomeII: 10.8% vs 5.4%, NS). No differences were found in IBS prevalence depending on cohabita-tion with the index case. Of all relatives meeting the Rome I and Rome II criteria, 40.4%and 69.4% respectively had consulted for bowel symptoms in the past year, and many ofthose who had not consulted had self-medicated (Rome I: 22.6%; Rome II: 54.5%). Relativeswho met Rome I and Rome II criteria showed worse QoL than general Spanish population.Patients with IBD had similar QoL than relatives who met Rome II criteria, but worsethan relatives who met Rome I criteria. The QoL worsening was associated with increasedconsumption of health resources (medical consultations and self-prescribed drugs) in relativesof patients with IBD. CONCLUSIONS: IBS prevalence in first-degree relatives of patientsdiagnosed with IBD is significantly elevated. It is significantly greater in first-degree bloodrelatives, which suggests the implication of genetic rather than psychological-environmentalfactors. Relatives of patients with IBD who meet the Rome I and Rome II criteria showworse QoL and use more healthcare resources for bowel symptoms than relatives who donot meet IBS criteria.

T2079

Reduced 5-Hydroxytryptamine (5-HT) Signaling Determines Stool Consistencyand Transit in Functional GI Patients With ConstipationChander Shekhar, Phillip J. Monaghan, Basma Issa, Peter J. Whorwell, Brian Keevil, JulieMorris, Lesley A. Houghton

Studies have shown that platelet depleted plasma (PDP) 5-HT concentration increases withmeal ingestion (1,2) and that this change (fasting to fed) is significantly reduced in IBS-Cpatients compared with controls (2,3). Furthermore, low levels of postprandial 5-HT (notreferenced to fasting) tend (p=.09) to associate with prolonged colonic transit, but onlywhen a mixed group of post-infective and IBS-C patients were assessed together (3). Ouraim was to explore this further, by assessing pre- and post-prandial PDP 5-HT concentrations,orocecal and colonic transit, and stool consistency in functional GI patients with constipation.Methods: 15 female patients (13 IBS-C and 2 functional constipation, aged 21-53yrs) and8 healthy females (aged 21-44 yrs) were recruited. Following a 7 day diary in which stoolconsistency (Bristol Stool Scale, BSS) was assessed, PDP 5-HT concentration was measuredunder both fasting (2hrs) and fed (4hrs) conditions. Within 2 weeks, orocecal (hydrogenbreath test) and colonic (radio-opaque markers for 3 days followed by X-ray) transit weredetermined. 5-HT concentration was assessed using rapid liquid chromatography tandemmass spectrometry (4). Results: Patients had significantly reduced 5-HT responses to mealingestion (mean increase from fasting (SD): + 0.96nmol/L(±5.81) v + 6.93nmol/L(±4.78);p=.02), delayed colonic (59.67hrs (±10.88) v 36.88hrs(±15.84); p=.001) but not orocecal(328.87min(±94.27) v 325.75min(±94.54); p=.941) transit, and harder stools (BSS:2.34(±1.17) v 3.8(±1.09); p=.008) compared with controls. Sub-grouping patients into thosewith severe (BSS ≤ 2) and mild (BSS>2) constipation, showed that those with severeconstipation had significantly reduced 5-HT responses to meal ingestion (-0.57nmol/L(±6.51); p=.04) and slower colonic (61.57hrs(±9.79): p=.004) but not orocecal(298.57min(±37.05); p=1.0) transit compared with controls. However, although patientswith mild constipation had slower colonic transit (58.0hrs(±12.16); p=.01), their orocecaltransit (355.38min(±121.97); p=1.0) and 5-HT responses to meal ingestion (2.29nmo/L(±5.17); p=.32) were no different from controls. Interestingly, postprandial PDP 5-HTlevels (not referenced to fasting) were no different between severe/mild constipated patientsand controls. Conclusions: In patients with constipation, the severity of their constipationis related to their 5-HT response to meal ingestion. The 5-HT response to meal ingestionis a better marker of constipation than actual postprandial 5-HT levels. Refs: (1) Gut2003;52:663; (2) Gastroenterol 2006;130:34; (3) Clin Gastroenterol Hepatol 2005;3:349;(4) J Chromatogr B 2009;877:2163

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