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Medical Care for Irritable Bowel Syndrome (IBS) in Japan Compared to theU.S.Motoyori Kanazawa, William E. Whitehead, Olafur S. Palsson, Marsha J. Turner, MasaeShinozaki, Yusuke Okuyama, Shin Fukudo

Background: It has been demonstrated that usual medical care for IBS emphasizes educationand lifestyle modification more than drugs in the US (Whitehead et al. Aliment PharmacolTher 2004). No studies have compared directly how IBS patients are managed in the USvs. other countries. Our aims were to compare the usual medical care for IBS in the USand Japan. Methods: 1762 patients in the US (73% of females) and 376 patients in Japan(50% of females) were recruited from primary care and GI clinics. They completed postalquestionnaires within two weeks after a doctor visit at which they received a diagnosis ofIBS. Questionnaires used in the Whitehead et al study were translated into Japanese andvalidated; they included the Rome II modular questions for IBS diagnosis, the IBS severityscale (IBS-SS), the IBS-QOL, ratings of confidence in their doctors (0 to 100) and satisfactionwith treatment (0 to 100). They also reported which treatments their doctors recommendedand whether they received education and reassurance about IBS. Results: IBS clinic patientsin Japan (n=200) were younger (41±17 vs. 51±14 yrs) and more likely to be males (62%vs. 23%) compared to US patients (n=665). There was no difference in overall IBS severity(230±112 in Japan vs. 239±116 in the US), but Japanese patients had lower IBS-QOL(69±22, vs. 73±21, p=0.01). Diet and exercise recommendations were less frequent in Japan(Table), perhaps reflecting lower rates of obesity. Drug treatment of IBS was more aggressivein Japan, with significantly greater use of anxiolytics. Motility agents were prescribed to71% of Japanese IBS patients but were not even on the formulary in the US clinics wherethis study was done. Japanese IBS patients were also more likely than US patients to receiveeducation (97% vs. 56%, p<0.01) and reassurance (74% vs. 48%, p<0.01). Japanese patientsreported greater confidence in their doctor's treatment recommendations (88±15 vs. 66±31,p<0.01) and greater satisfaction with treatment (73±20 vs. 65±26, p<0.01). Conclusions:IBS is treated more aggressively in Japan where the majority of IBS clinic patients are males,and Japanese patients are more satisfied with their treatment. [Supported by R01 DK31369]Treatment recommended by doctors for IBS symptoms

*p<0.05, **p<0.01 vs. US patients

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Disturbed Sleep Worsens IBS Pain Symptoms: an Effect of Gastrointestinal(GI) Specific Anxiety?Ami Patel, Benjamin Cassell, Mrudula Kumar, C. Prakash Gyawali, Gregory S. Sayuk

BACKGROUND: Sleep disturbances (SD) are common, affecting up to one-half of thepopulation, and perhaps even greater numbers of irritable bowel syndrome (IBS) patients.Preliminary data suggests SD may contribute to visceral and somatic symptom burdens inIBS (Kumar M, et al. DDW 2010), and to anxiety experiences in psychiatric populations.We sought to determine: 1) the effect of SD on IBS symptoms and IBS-specific quality oflife (IBS-QOL) and, 2) the role of GI-specific anxiety as a mediator of the relationship ofSD and IBS symptoms. METHODS: Sleep patterns of IBS subjects (Rome III) were comparedto healthy controls via wrist-mounted actigraphy data (Motionlogger, Ambulatory Mon-itoring, Inc.) collected over a 7-day period. Actigraphy correlates well with polysomnography,and offers the advantage of ‘real world' testing. Daily logs of bowel pain (severity and distress;10-pt Likert), stool pattern (Bristol stool scale) and supporting symptoms (bloating, gas,urgency, mucus; 5-pt Likert) were kept during actigraphy. All subjects completed a validatedIBS symptom measure (GI Symptom Rating Scale-IBS, GSRS-IBS), the Visceral SensitivityIndex (VSI) as a measure of GI-specific anxiety, and the IBS-QOL disease specific quality-of-life instrument. RESULTS: 43 subjects, 20 IBS (45.5 ±12.4 yrs, 18 F) and 23 healthycontrols (45.7 ±12.5 yrs, 19 F) completed 7 days of sleep monitoring. IBS subjects sleptlonger than controls (mean sleep 8.1 ±2.2 hrs vs. 6.9 ±1.8 in controls; p <0.001). However,IBS subjects demonstrated more waking episodes during sleep (WEDS, 11.7 ±7.4 vs. 8.9±6.7 in controls, p =0.001), and in turn experienced shorter mean undisturbed sleep periods(63.5 ±43.3 vs. 99.7 ±95.8 min, p<0.001). In the IBS population, shorter mean undisturbedsleep episodes and WEDS number correlated with abdominal pain (p=0.04 and p=0.02,respectively) and GI distress (p=0.003 and p=0.001) the following day, but not with bloating,gas, mucus, urgency, or Bristol stool scores (p>0.05 for each). In contrast, sleep parameterswere not significantly associated with any bowel measures in controls (p>0.05 for each).Among IBS patients, WEDS number significantly correlated with both IBS-QOL scores (r=-0.566, p<0.001) and VSI scores (r=0.467, p<0.001). Multivariate analysis examining theeffect of disturbed sleep and GI-specific anxiety on IBS-related pain found only the VSIscore (B=0.108, p<0.001) but not WEDS (B=0.045, P=0.29) to be a significant predictor ofIBS pain scores. CONCLUSIONS: IBS subjects suffer more sleep disturbances despitespending greater amounts of time dedicated to sleep, correlating with greater IBS-relatedpain, distress, and GI-specific anxiety, as well as poorer IBS-related QOL. GI-specific anxiety,

S-10AGA Abstracts

as determined by VSI, may mediate these observed relationships between sleep disturbancesand IBS symptoms.

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Which Psychological Factors Exacerbate Irritable Bowel Syndrome? Test of aComprehensive ModelMiranda A. van Tilburg, Olafur S. Palsson, William E. Whitehead

INTRODUCTION: Psychological disturbances are common in IBS patients and influencebowel symptoms as well as disability (Palsson & Drossman, Gastroenterol Clin North Am,2005). Many psychological factors have been explored but it is not clear which ones are themost important in explaining exacerbation of IBS. Given the myriad of possible interactions,mediators and moderators, an overarching model of psychological factors in IBS is needed.Such a model could identify treatment strategies and further inform research. The purposeof the current work was to test and refine a model of psychological influences on IBSsymptoms. METHODS: N=286 IBS patients (Mean age= 34.6 years; 81.5% female, 71.3%Caucasian, 19.2% African American, 3.5% Hispanic) completed questionnaires on IBS sever-ity (IBS Severity Scoring System), Abuse history, Stressful life events (Family Inventory of LifeEvents), Neuroticism (NEO-PI), Psychological distress (Anxiety subscale of Brief SymptomInventory-18), Somatization (Brief Symptom Inventory-18) and Catastrophizing (CopingStrategies Questionnaire). We hypothesized that stable psychological variables (Neuroticism,Abuse history, Stressful life events) influence psychological variables that are more amenableto change (Psychologcial distress, Somatization, Catastrophizing), and all these variablesinfluence IBS severity. Path analysis was used to test our model. RESULTS: The final model,after removing non-significant associations, is given in the Figure and performed well (Chi2(df=5)= 2.77; p=0.74; RMSEA < .05). Catastrophizing and Somatization were associatedwith IBS severity. Psychosocial distress had an indirect effect on IBS symptoms throughCatastrophizing and Somatization, while Psychosocial distress was in turn predicted byNeuroticism and Stressful life events. When combined, these variables predicted 36% ofthe variance in IBS severity. CONCLUSION: While cause-and-effect cannot be determinedfrom these cross-sectional data, the outcomes suggest that the two most important variablesin predicting IBS severity are catastrophizing and somatization and that they mediate theeffects of all the other psychological variables. However, psychological distress plays animportant intermediate role in the model, increasing Catastrophizing and Somatization andmediating the impact of Neuroticism and Stressful life events. This suggests that the mostfruitful approach to curb negative effects of psychological factors on IBS is to reduce Catastro-phizing and Somatization. [Supported by R01DK31369 and UL1RR025747]

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Ursodeoxycholic Acid Protects Against Deoxycholic Acid-Induced DNADamage and NF-κB Activation in Barrett's Metaplasia In Vitro and In VivoSui Peng, Xiaofang Huo, Davood Rezai, Qiuyang Zhang, Xi Zhang, Chunhua Yu, KiyotakaAsanuma, Edaire Cheng, David H. Wang, Stuart J. Spechler, Rhonda F. Souza

Introduction: In earlier studies, we showed that a 5-minute perfusion of Barrett's esophaguswith deoxycholic acid (DCA, a bile acid found in refluxed gastric juice) caused DNA damageand activated the NF-κB pathway in the metaplastic epithelium. In Vitro studies showedthat this NF-κB activation enabled Barrett's cells to resist apoptosis that otherwise might betriggered by DCA-induced DNA damage, a feature that might predispose to malignancy.We also showed that esophageal perfusion with ursodeoxycholic acid (UDCA) did not causeDNA damage or activate NF-κB in Barrett's metaplasia. To explore a potential chemopreven-tive role for UDCA, we now have studied effects of UDCA treatment on DCA-induced DNAdamage and NF-κB activation in patients with Barrett's esophagus, and we have exploredthe mechanism underlying those effects in benign Barrett's cell lines. Methods: Duringendoscopy in 3 patients with Barrett's esophagus, a perfusion catheter was passed throughthe biopsy channel, and the Barrett's metaplasia was perfused with DCA (250 μM) for 5minutes. Biopsy specimens were taken from the Barrett's metaplasia at baseline and afterthe DCA perfusion. Patients were then treated with UDCA (10 mg/kg po) for 8 weeks, andthe endoscopic DCA perfusion and biopsy procedures were repeated. In Vitro, two benignBarrett's epithelial cell lines (BAR-T and BAR-T10) were exposed to DCA (250 μM) for 5minutes with or without pretreatment by UDCA (300 μM) for 24 hours. We then determined:1) DNA damage by p-H2AX expression, 2) reactive oxygen species (ROS) generation by theROS Detection Kit, and 3) protein expression levels of glutathione peroxidase 1 (GPX1, ananti-oxidant) and p-p65 (an active subunit of NF-κB) by Western blotting. Western blotsfor p-H2AX and p-p65 were densitized, and levels are expressed as relative intensity units(RIU). Results: Esophageal perfusion with DCA increased expression of p-H2AX (.65 ±.18%(SEM) to 2.25 ±.76%RIU) and p-p65 (.87 ±.80% to 1.57 ±.1.11%RIU) in Barrett's metaplasia.After 8 weeks of UDCA treatment, in contrast, DCA perfusion caused no increase in p-H2AX (1.01 ±.47% to .90 ±.54% RIU) or p-p65 (.71 ±.35% to .12 ±.095% RIU). In bothcell lines, DCA markedly increased the expression levels of p-H2AX and p-p65. Followingpretreatment with UDCA, in contrast, DCA caused no increase in those same levels. DCAcaused a significant increase in ROS generation that was inhibited by UDCA pretreatment,and UDCA pretreatment caused a marked increase in expression levels of GPX1.Conclusion:Both In Vitro and In Vivo, UDCA protects against DCA-induced DNA damage and activationof the NF-κB pathway. In Barrett's cells, UDCA blocks DCA-induced ROS generation andincreases expression of the anti-oxidant GPX1. This study elucidates molecular pathwayswhereby UDCA treatment might protect against carcinogenesis in Barrett's metaplasia.