Obesity Is Associated With Increased Transient Lower Esophageal Sphincter Relaxation

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1 GASTROENTEROLOGY 2007;132: Obesity Is Associated With Increased Transient Lower Esophageal Sphincter Relaxation JUSTIN CHE YUEN WU, LIK MAN MUI, CARRIAN MAN YUEN CHEUNG, YAWEN CHAN, and JOSEPH JAO YIU SUNG Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Background & Aims: Obesity has been associated with gastroesophageal reflux disease (GERD) and its complication, but the mechanism is unclear. We evaluated the association between obesity and function of lower esophageal sphincter (LOS) in subjects without GERD. Methods: We prospectively recruited consecutive obese (BMI >30) patients referred for weight reduction procedure and age- and sex-matched overweight (BMI 25 30) and normal weight (BMI >20 and <25) subjects. Exclusion criteria included esophagitis, reflux symptoms, use of proton pump inhibitor, hiatus hernia >2 cm, and diabetes mellitus with microvascular complication. All participants underwent combined 2-hour postprandial esophageal manometry and ph monitoring after a standard test meal followed by 24-hour ambulatory ph monitoring. Results: Eighty-four subjects (obese, 28; overweight, 28; normal weight, 28) were studied. All 3 groups had comparable mean LOS pressure, LOS length, and peristaltic function. During the postprandial period, both obese and overweight groups had substantial increase in 2-hour rate of transient lower esophageal sphincter relaxation (TLOSR) (normal weight: vs overweight: vs obese: , P <.001), proportion of TLOSR with acid reflux (normal weight: 17.6% 22.0% vs overweight 51.8% 22.5% vs obese: 63.5% 21.7%, P <.001), and gastroesophageal pressure gradient (GOPG) (normal weight: mm Hg vs overweight: mm Hg vs obese: mm Hg, P <.001). Using multiple regression model, BMI (r 2 : 0.70, B: 0.28, 95% CI: , P <.001) and waist circumference (r 2 : 0.65, unstandardized regression coefficient [B]: 0.10, 95% CI: , P <.001) were significantly correlated with TLOSR. Conclusions: Obesity is associated with increased TLOSR and acid reflux during the postprandial period in subjects without GERD. Abnormal postprandial LOS function may be an early event in the pathogenesis of obesity-related GERD. The worldwide prevalence of being overweight and obesity has been increasing at an alarming rate over the last decade, indiscriminately affecting populations of both higher and lower middle income countries. 1 The rise in obesity coincides with rising prevalence of gastroesophageal reflux disease (GERD). 2,3 A positive association between obesity and GERD has been reported in many epidemiologic studies. A high body mass index (BMI) is associated with an increased risk of GERD, 4 6 and a dose-response relationship exists between increasing BMI and prevalence of GERD 7,8 Given the similar secular trends of prevalence and the positive epidemiologic associations, obesity may in some way promote the development of GERD. The cause for the increased prevalence of GERD among the obese remains speculative. One of the most probable mechanisms is the increase in mechanical stress imposed on the gastroesophageal junction (GOJ) and the predisposition to hiatus hernia. Using high-resolution manometry techniques, it has recently been shown that obese subjects are more likely to have GOJ disruption, hiatus hernia, and augmented intragastric pressure and gastroesophageal pressure gradient (GOPG). 9 Transient lower esophageal sphincter relaxation (TLOSR) is the most important mechanism of gastroesophageal reflux. 10 Patients with GERD have significantly more frequent TLOSR associated with acid reflux, regardless of the presence of hiatus hernia. 11 Although hiatus hernia and esophageal peristaltic dysfunction play an important role in severe reflux esophagitis, TLOSR may be the only mechanism of reflux observed in patients with milder reflux disease. Data on the effect of obesity on TLOSR, however, are still lacking. In this study, we set out to evaluate the relationship between obesity and TLOSR in the absence of hiatus hernia. We studied the effect of obesity on function of GOJ in subjects without GERD. Materials and Methods Subjects We prospectively recruited consecutive obese (BMI 30 kg/m 2 ) patients who were referred for globus, noncardiac chest pain, or preoperative assessment of Abbreviations used in this paper: BMI, body mass index; GERD, gastroesophageal reflux disease; GOJ, gastroesophageal junction; GOPG, gastroesophageal pressure gradient; LOS, lower esophageal sphincter; TLOSR, transient lower esophageal sphincter relaxation by the AGA Institute /07/$32.00 doi: /j.gastro

2 884 WU ET AL GASTROENTEROLOGY Vol. 132, No. 3 weight reduction procedures because of moderate to severe obesity. During the same study period, nonobese patients with globus and noncardiac chest pain were recruited as controls. All patients with globus and noncardiac chest pain had failure of symptom response to an 8-week therapeutic trial of proton pump inhibitor. The controls were further classified into (1) normal weight (BMI 25) and (2) overweight (BMI 25 30) according to the World Health Organization (WHO) classification of body weight. 12 All 3 groups of patients (obese, overweight, and normal weight) were age and sex matched. Patients with endoscopic erosive esophagitis as defined by Los Angeles classification, weekly attacks of heartburn and acid regurgitation, need of proton pump inhibitor or prokinetic agent for upper gastrointestinal symptom, achalasia, and sliding hiatus hernia, which was defined as longitudinal separation of diaphragmatic hiatus and GOJ by 2 cm or more, were excluded from the study. Other exclusion criteria included previous gastric surgery and diabetes mellitus with established microvascular complication. The study was approved by the Clinical Ethics Committee of The Chinese University of Hong Kong, and written informed consent was obtained for all participants. Clinical Assessment All subjects completed a structured questionnaire on demographics, medical history, and gastrointestinal symptoms. Heartburn and acid regurgitation were rated using a 4-point Likert scale (0, asymptomatic; 1, mild only recall on questioning and not affect daily activity; 2, moderate constantly aware of the symptom but not affect daily activity; 3, severe interfere with daily activity). Patients with symptom scores of 1 or above were excluded from the study. Anthropometric measurements including BMI and waist circumference were recorded by a research nurse (C.M.Y.C.) before manometry testing. Waist circumference was measured at the greatest abdominal circumference with a measuring tape. Diagnosis of obstructive sleep apnea was confirmed by polysomnography. Endoscopy was then performed prior to a therapeutic trial of proton pump inhibitor to exclude reflux esophagitis, hiatus hernia, and peptic ulcer. Esophageal Manometry and ph Monitoring and 24-Hour Ambulatory ph Monitoring Esophageal manometry was performed with a 4.4-mm 10 1 channel multilumen assembly that incorporated a sleeve sensor (A-E2-LOSS-1; Dentsleeve Pty Ltd, Adelaide, South Australia). The sleeve sensor monitored lower esophageal sphincter (LOS) pressure. A side hole 1 cm below the distal margin of the sleeve recorded intragastric pressure. Side holes at 3-cm intervals, starting at the proximal margin of the sleeve, recorded esophageal body peristalsis, and a side hole in the pharynx recorded swallowing. The sleeve and gastric side hole were perfused with degassed distilled water at 0.45 ml/min and the esophageal side holes at 0.3 ml/min by a low compliance manometric perfusion pump. The pharyngeal side hole was perfused by air at 8 ml/min. An additional infusion port was located at midesophagus (11 cm above LOS). Pressures were detected by external transducers with output to a computerized acquisition system. Vertical perfusion baseline was determined to offset any hydrostatic pressure gradient among perfusion side holes at different height. Esophageal ph was measured with an antimony electrode (Medtronic Functional Diagnostics A/S, Tonsbakken, Denmark). Combined measurement of esophageal pressures and ph were synchronized by a digital data logger (Polygraf; Medtronic, Denmark). The Table 1. Comparison of Demographics, Anthropometric Measurements, and Fasting Motility Parameters Among 3 Groups Control Overweight Obese P value No Male sex (%) 16 (57) 16 (57) 16 (57) 1.00 a Age, yr 41.8 (7.5) 43.1 (8.3) 40.9 (7.5).92 Indication of esophageal manometry and ph study Noncardiac chest pain (%) 12 (43) 5 (18) 0 (0) Globus (%) 16 (57) 20 (71) 0 (0) Preoperative assessment of bariatric procedure (%) 0 (0) 3 (1) 28 (100) Diabetes mellitus (%) 2 (7.1) 3 (10.7) 4 (14.1).69 a Obstructive sleep apnea (%) 0 (0) 0 (0) 6 (21.4).002 a Body mass index (SE) 22.1 (1.6) 27.4 (1.4) 38.2 (6.3).001 Waist circumference, cm (SE) 72.0 (5.3) 86.4 (3.9) (16.1).001 LOS length, cm (SE) 3.4 (0.7) 3.8 (0.6) 3.6 (0.5).69 LOS pressure, mm Hg (SE) 16.9 (2.8) 17.3 (2.9) 16.3 (3.1).57 Total number of TLOSR in 1 hour 0.8 (0.2) 0.9 (0.3) 1.0 (0.3) 34 Fasting GOPG, mm Hg (SE) 3.5 (0.9) 4.0 (1.3) 4.2 (1.8).13 Normal primary peristalsis (%) 88.4 (5.3) 91.1 (6.5) 88.1 (5.3) 63 Normal secondary peristalsis (%) 66.9 (12.5) 64.1 (13.1) 69.2 (17.2) 44 NOTE. Data expressed as mean (SEM). Fasting (preprandial). a 2 test.

3 March 2007 OBESITY AND TLOSR 885 data were digitized and displayed using commercially available software (Polygram 2000; Medtronic). All subjects were studied in an upright position after overnight fast. After transnasal intubation, the position and length of LOS were determined using the station pull-through technique at 1-cm intervals, and the sleeve sensor was positioned across the LOS. The ph electrode was affixed to the manometric assembly so that it was positioned 5 cm above the proximal margin of the lower esophageal sphincter. After a 10-minute period of adaptation, 10 water swallows of 5 ml each were then given to test primary peristalsis of esophageal body and LOS relaxation in the upright position. Secondary peristalsis was evaluated by esophageal distention with 5, 20-mL boluses of air injected through the infusion port within 1 second. The monitoring continued for 1 hour for measurement of TLOSR at fasting state. After fasting measurements, patients were given a standard soft mixed nutrient test meal (400 kcal, 55% fat) consisting of 150 ml Enercal, savory mince, and porridge. Recordings were then continued for 2 hours. On completion of postprandial ph and manometric studies, another ph electrode was inserted and positioned at 5 cm above the upper border of the LOS for 24-hour ambulatory monitoring. Data acquisition was performed using a portable data logger (Microdigitrapper MK III; Medtronic), and the data were subsequently uploaded and analyzed using commercially available software (EsopHogram; Medtronic). Data Analysis Both fasting and 2-hour postprandial data were analyzed by a single investigator (J. W.), who was blinded to the BMI of subjects. End expiratory basal LOS pressure was referenced to end expiratory intragastric pressure and was determined at 1-minute intervals over a 10- minute period. For primary and secondary peristalsis, a peristaltic sequence was regarded as complete if the amplitude of each propagated pressure wave was 10 mm Hg in the proximal 2 and 30 mm Hg in the distal 3 esophageal body channels. Criteria for failed peristalsis included pressure wave of low amplitude ( 10 mm Hg in proximal or 30 mm Hg in distal channels) or propagating velocity 10 cm/second). GOPG was defined as the mean difference between end-expiratory intragastric pressure and end-expiratory esophageal pressure as measured by gastric side hole and distal esophageal side hole located 4 cm above the upper border of the LOS, respectively. It was determined at 1-minute intervals over a 10-minute period. A positive pressure gradient denoted higher intragastric pressure compared with intraesophageal pressure. TLOSR was defined according to the criteria defined by Holloway et al. 13 LOS relaxations that lasted more than 15 seconds, which were associated with a swallow within 4 seconds before or 2 seconds after the onset of an LOS relaxation, were also included as TLOSRs. 14 Acid reflux was defined as a drop in esophageal ph below 4 for at least 5 seconds or, if basal esophageal ph was already below 4, as a further drop in ph of at least 1 ph unit. Slow downward drifts of ph from baseline to 4 or below were not considered as acid reflux in the postprandial study. Statistical Analyses The 3 groups of patients were compared for basal LOS pressure, percentages of primary and secondary peristalsis, GOPG, number of TLOSRs, and proportions of TLOSRs associated with acid reflux. For 24-hour esophageal acid exposure, semiautomated analysis was per- Figure 1. Scatter plot of (A) total number of TLOSR in 2 hours and (B) gastroesophageal pressure gradient (GOPG) between normal weight controls and overweight and obese groups. The error bars denote mean 2 SEM.

4 886 WU ET AL GASTROENTEROLOGY Vol. 132, No. 3 formed with the aid of commercially available software (EsopHogram; Medtronic). Any reflux episode, defined as ph 4, with duration less than 5 seconds was judged to be an artifact. Variables of esophageal acid exposure included total, 2-hour postprandial and upright percentages time ph 4. The data are presented as mean (SEM) and compared using 1-way analysis of variance (ANOVA) (SPSS 11.5, SPSS Inc, Chicago, IL). The relationship between anthropometric measurements (BMI, waist circumference) and motility parameters was evaluated by linear regression analysis. After testing for colinearity, multiple regression analysis including age, gender, and obstructive sleep apnea was performed. Pearson correlation coefficients and regression coefficients were determined, and a P value of less than.05 was considered statistically significant. Results From August 2003 to September 2005, 28 obese subjects, 28 overweight subjects, and 28 normal weight controls were studied. Sixteen subjects in each group were male. The demographics and anthropometric data are presented in Table 1. Noncardiac chest pain was the indication for the motility study in 12 (43%) normal weight subjects and 5 (18%) overweight subjects. None of the subjects with globus and noncardiac chest pain had symptom response to proton pump inhibitors. Six (21.4%) patients in the obese group and none in the overweight or normal weight group had obstructive sleep apnea (P.002). Both obese and overweight groups had significantly larger waist circumferences as compared with the control groups (P.001). During the preprandial period, the 3 groups had comparable mean basal LOS pressure (P.57), GOPG (P.13), mean LOS length (P.69), and mean percentages of primary peristalsis (P.63) and secondary peristalsis (P.44) (Table 1). There was also no difference in rate of TLOSR (P.34). During the 2-hour postprandial period, however, obese and overweight subjects had a higher rate of TLOSRs (control: vs overweight: vs obese: , P.001) than the controls (Figure 1). The proportion of TLOSR with acid reflux was significantly higher in both obese (63.5% 21.7%) and overweight (51.8% 22.5%) subjects as compared with controls (17.6% 22.0%, P.001), but there was no significant difference in this proportion between obese and overweight subjects (P.15) (Table 2). Postprandial GOPG increased substantially in both obese and overweight subjects and was higher than in controls (control: mm Hg vs overweight: mm Hg vs obese: mm Hg, P.001). During ambulatory ph monitoring, total, 2-hour postprandial and upright esophageal acid exposure times were also significantly higher in both overweight and obese subjects as compared with controls (Table 2). The rate of postprandial TLOSRs correlated strongly with anthropometric measurements. BMI correlated significantly with number of TLOSRs (r 0.81, P.001) and number of TLOSRs associated with acid reflux (r 0.88, P.001) (Figure 2). Similarly, waist circumference also correlated significantly with number of TLOSRs (r 0.84, P.001) and number of TLOSRs with acid reflux (r 0.89, P.001) (Figure 3). Postprandial GOPG correlated significantly with total number of TLOSR (r 0.83, P.001) and TLOSR with reflux (r 0.84, P.001). Using multiple regression model adjusted for age, gender, and obstructive sleep apnea, the regression coefficients of BMI and waist circumference for TLOSR were 0.28 (95% CI: , P.001) and 0.1 (95% CI: , P.001), respectively. Discussion Obesity has been implicated as a major risk factor of GERD and its complication. Many studies have reported an association between obesity, hiatus hernia, and various motility dysfunctions of the upper gastrointestinal tract in GERD patients. However, it is arguable whether obesity predisposes to these conditions or whether they merely coexist in GERD. To solve this controversy, we set out to evaluate the relationship between obesity and functional integrity of GOJ in subjects without GERD. In this study, we evaluated the relation- Table 2. Comparison of Postprandial TLOSR, GOPG, and 24-Hour Esophageal Acid Exposure Among 3 Groups Control Overweight Obese P value No Total number of TLOSR in 2 hours 2.1 (1.2) 3.8 (1.6) 7.3 (2.0).001 Total number of TLOSR with acid reflux in 2 hours 0.5 (0.6) 2.0 (1.1) 4.5 (1.8).001 Proportion of TLOSR with acid reflux in 2 hours (%) 17.6 (22.0) 51.8 (22.5) 63.5 (21.7).001 a Postprandial GOPG (mm Hg) 4.5 (1.2) 7.1 (1.4) 10.0 (1.5).001 Ambulatory esophageal ph monitoring Total % time ph (0.2) 0.7 (0.4) 2.3 (1.1).001 b 2-Hour ambulatory postprandial % time ph (0.6) 2.8 (1.1) 6.8 (2.6).001 Ambulatory upright % time ph (0.3) 1.4 (0.7) 4.5 (0.7).001 NOTE. Data expressed as mean (SEM). Post hoc analysis using Bonferroni s method: a P.15 for overweight vs obese group; b P.017 for control vs overweight group; P.001 for other post hoc analyses.

5 March 2007 OBESITY AND TLOSR 887 in the Chinese population, it is unlikely that these patients were suffering from GERD. In this study, 3 groups of subjects had comparable esophageal peristaltic function, LOS length, and basal pressure during the fasting period. However, rates of TLOSR were substantially higher in overweight and obese subjects during the postprandial period. This finding suggests that dysfunction of TLOSR may be the earliest disruption in functional integrity of the antireflux barrier in obesity, which heralds hiatus hernia and other motility dysfunction. The reason for the increased rate of postprandial TLOSRs in obese subjects is unclear. Although current evidence argues against a major difference in the rate of TLOSRs between normal subjects and patients with GERD, these studies have not stratified for BMI. 15 Because gastric distention is a major mechanism of postprandial TLOSRs, it has been speculated that obese pa- Figure 2. The correlation between body mass index and (A) total number of TLOSR in 2 hours and (B) number of TLOSR with acid reflux in 2 hours. ship between obesity and esophageal motility function, notably TLOSR, in subjects without GERD and hiatus hernia. We observed that obesity was associated with increased TLOSR, which was accompanied with increased postprandial gastroesophageal reflux and esophageal acid exposure. The frequency of TLOSR was strongly correlated with both BMI and waist circumference. We excluded those with hiatus hernia to eliminate its effect on function of GOJ. Although symptoms such as globus and noncardiac chest pain could be atypical manifestation of GERD, all of these patients failed to respond to a therapeutic trial of acid suppression, and no symptom-reflux association was demonstrated during esophageal ph monitoring. Given the low prevalence of GERD Figure 3. The correlation between waist circumference and (A) total number of TLOSR in 2 hours and (B) number of TLOSR with acid reflux in 2 hours.

6 888 WU ET AL GASTROENTEROLOGY Vol. 132, No. 3 tients tend to overeat, leading to a more distended proximal stomach and increased postprandial TLOSR. In our study, however, all study participants were given a test meal of standard volume and caloric content. Therefore, the higher rate of TLOSR observed in this study could not be explained by excessive calorie intake, over distention of stomach, or hypersensitivity of gastric mechanical stretch receptors. It has also been suggested that obstructive sleep apnea may be associated with GERD. 16 In this study, however, no association between obstructive sleep apnea and TLOSR was observed. Our finding suggests that obstructive sleep apnea may be an epiphenomenon in the relationship between obesity and GERD. One of the probable mechanisms of increased postprandial TLOSR and GOR in obese subject is increased intragastric pressure. This speculation is supported by the significant correlation between TLOSR with GOPG, BMI, and waist circumference in a dose-effect relationship observed in this study. The accuracy of intragastric pressure and GOPG measurement in this study could be limited by the use of a single gastric side hole of waterperfused manometry, which was subject to hydrostatic effects and difficulty to reference intragastric pressure to atmospheric pressure. However, our findings are compatible with a previous study by Pandolfino et al using high-resolution solid-state manometry that reported significant correlation between intragastric pressure and GOPG with BMI and waist circumference. 9 TLOSR is a neurally mediated reflex triggered by mechanical distention of the proximal stomach. 17,18 Both stretch and tension mechanoreceptors at the proximal stomach have been implicated to play an important role in TLOSR, although a recent study suggests that stretch receptors seem to be more relevant. 19 It has been observed that stepwise pressure-controlled barostat distention of the proximal stomach provokes TLOSR, which is strongly correlated with intragastric pressure. 20 Furthermore, intragastric pressure may also be the culprit of the increased proportion of TLOSR with acid reflux observed in obese and overweight subjects. It has been reported that transsphincteric pressure gradient but not gastric volume is greater in TLOSRs associated with acid gastroesophageal reflux. 21 We postulate that higher postprandial intragastric pressure leads to more intense stimulation on both stretch and tension mechanoreceptors in the proximal stomach, which provokes more postprandial TLOSRs in abdominal obesity. The higher pressure gradient between the stomach and the esophagus also contributes to a higher proportion of TLOSR with acid reflux. There are issues that remain unresolved in this study. First, the status of nonacidic and air reflux in aggravated postprandial TLOSR related to obesity needs to be elucidated using impedance monitoring. Second, it is still unclear whether weight reduction can reverse these early functional changes of the LOS before irreversible disruption of the GOJ integrity sets in. A follow-up study on our obese patients after weight reduction procedure is warranted. Last, increased availability of unbuffered acidic gastric content at the GOJ has been reported in GERD patients. 22 Further studies are needed to evaluate the role of abdominal obesity and increased intragastric pressure in topographic distribution of gastric acid in causing GERD. In conclusion, obesity is associated with excessive TLOSR during the postprandial period, which results in elevated esophageal acid exposure in subjects without GERD. Our findings suggest that abnormal postprandial LOS function may be an early event in the pathogenesis of obesity-related GERD. References 1. WHO/NUT/NCD. Obesity: preventing and managing the global epidemic. Report of a WHO consultation on obesity Geneva: WHO, Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastrooesophageal reflux disease: a systematic review. Gut 2005;54: Locke GR, Talley NJ, Fett SL, et al. Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 1999;106: Fisher BL, Pennathur A, Mutnick JL, et al. Obesity correlates with gastroesophageal reflux. Dig Dis Sci 1999;44: Nilsson M, Lundegardh G, Carling L, et al. Body mass and reflux oesophagitis: an oestrogen-dependent association? Scand J Gastroenterol 2002;37: Diaz-Rubio M, Moreno-Elola-Olaso C, Rey E, et al. Symptoms of gastro-oesophageal reflux: prevalence, severity, duration and associated factors in a Spanish population. Aliment Pharmacol Ther 2004;19: El-Serag HB, Graham DY, Satia JA, et al. Obesity is an independent risk factor for GERD symptoms and erosive esophagitis. Am J Gastroenterol 2005;100: Murray L, Johnston B, Lane A, et al. Relationship between body mass and gastro-oesophageal reflux symptoms: The Bristol Helicobacter Project. Int J Epidemiol 2003;32: Pandolfino JE, El-Serag HB, Zhang Q, et al. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology 2006;130: Dent J, Holloway RH, Toouli J, et al. Mechanisms of lower oesophageal sphincter incompetence in patients with symptomatic gastrooesophageal reflux. Gut 1988;29: Sifrim D, Holloway R. Transient lower esophageal sphincter relaxations: how many or how harmful? Am J Gastroenterol 2001; 96: WHO. WHO, Physical status: the use and interpretation of anthropometry. Report of a WHO expert consultation. WHO Technical Report Series Number 854. Geneva: World Health Organization, Holloway RH, Penagini R, Ireland AC. Criteria for objective definition of transient lower esophageal sphincter relaxation. Am J Physiol 1995;268:G128 G van Herwaarden MA, Samsom M, Smout AJ. Excess gastroesophageal reflux in patients with hiatus hernia is caused by mechanisms other than transient LES relaxations. Gastroenterology 2000;119: Schoeman MN, Tippett MD, Akkermans LM, et al. Mechanisms of gastroesophageal reflux in ambulant healthy human subjects. Gastroenterology 1995;108:83 91.

7 March 2007 OBESITY AND TLOSR Orr WC, Heading R, Johnson LF, et al. Review article: sleep and its relationship to gastro-oesophageal reflux. Aliment Pharmacol Ther 2004;20(Suppl 9): Holloway RH, Hongo M, Berger K, et al. Gastric distention: a mechanism for postprandial gastroesophageal reflux. Gastroenterology 1985;89: Kahrilas PJ, Shi G, Manka M, et al. Increased frequency of transient lower esophageal sphincter relaxation induced by gastric distention in reflux patients with hiatal hernia. Gastroenterology 2000;118: Penagini R, Carmagnola S, Cantu P, et al. Mechanoreceptors of the proximal stomach: role in triggering transient lower esophageal sphincter relaxation. Gastroenterology 2004;126: Scheffer RC, Akkermans LM, Bais JE, et al. Elicitation of transient lower oesophageal sphincter relaxations in response to gastric distention and meal ingestion. Neurogastroenterol Motil 2002; 14: Scheffer RC, Gooszen HG, Hebbard GS, et al. The role of transsphincteric pressure and proximal gastric volume in acid reflux before and after fundoplication. Gastroenterology 2005;129: Fletcher J, Wirz A, Young J, et al. Unbuffered highly acidic gastric juice exists at the gastroesophageal junction after a meal. Gastroenterology 2001;121: Received August 29, Accepted November 27, Address requests for reprints to: Justin C. Y. Wu, MD, Department of Medicine and Therapeutics, 9/F, Clinical Science Building, Prince of Wales Hospital, Shatin, Hong Kong. justinwu@cuhk.edu.hk; fax: (852) The authors thank Prof Richard Holloway of Royal Adelaide Hospital for advice on manuscript writing.