Obesity Is Associated With Increased Transient Lower Esophageal Sphincter Relaxation. Introduction. Predisposing factor. Introduction.

Transcription

1 Obesity Is Associated With Increased Transient Lower Esophageal Sphincter Relaxation Gastro Esophageal Reflux Disease (GERD) JUSTIN CHE-YUEN WU, et. al. The Chinese University of Hong Kong Gastroenterology, 2007 Presented by Kanya Bunnan SIPS/M 1 2 Predisposing factor GERD The worldwide prevalence of being overweight and obesity WHO, 1998 The rise in obesity coincides with rising prevalence of gastroesophageal reflux disease (GERD) Dent J, et al and Locke GR, et al Body mass index (BMI) risk of GERD Fisher BL, et al. 1999, Nilsson M, et al and Diaz-Rubio M, et al A dose-response relationship exists between BMI and prevalence of GERD Factor cause of GERD among the obese mechanisms mechanical stress El-Serag HB, et al and Murray L, et al Obesity may in some way promote the development of GERD gastroesophageal junction (GOJ) predisposition to hiatus hernia 5 6

2 High-resolution manometry techniques Obese subjects : GOJ disruption Hiatus hernia Augmented intragastric pressure and gastroesophageal pressure gradient (GOPG) Pandolfino JE, et al Transient lower esophageal sphincter relaxation (TLOSR) is the most important mechanism of gastroesophageal reflux Dent J, et. al., 1988 Patients with GERD have significantly more frequent TLOSR associated with acid reflux, regardless of the presence of hiatus hernia Sifrim D, et al Hiatus hernia and esophageal peristaltic dysfunction play an important role in severe reflux esophagitis Aim To evaluate the relationship between obesity and TLOSR TLOSR may be the only mechanism of reflux To evaluate the effect of obesity on function of GOJ in subjects without GERD 9 10 Inclusion critiria Exclusion critiria Obese patients (BMI >30 kg/m 2 ) Endoscopic erosive esophagitis Recruited consecutive obese patients Globus, noncardiac chest pain, or preoperative assessment of weight reduction procedures 11 Achalasia Sliding hiatus hernia Previous gastric surgery Diabetes mellitus with established microvascular complication 12

3 Controls Nonobese patients with globus and noncardiac chest pain Normal weight (BMI <25) Overweight (BMI 25-30) WHO classification of body weight Clinical Assessment A structured questionnaire (demographics, medical history, gastrointestinal symptoms) Heartburn and acid regurgitation were rated using a 4-point Likert scale The study was approved by The Clinical Ethics Committee of The Chinese University of Hong Kong or were excluded 14 Anthropometric measurements including BMI and waist circumference Waist circumference tape measuring Esophageal Manometry and ph Monitoring and 24-Hour Ambulatory ph Monitoring Esophageal manometry a 4.4-mm 10+1 channel multilumen assembly that incorporated a sleeve sensor Obstructive sleep apnea polysomnography Endoscopy performed prior to a therapeutic trial of proton pump inhibitor 15 The sleeve sensor sphincter (LOS) pressure lower esophageal 16 perfused by air at 8 ml/min recorded swallowing perfused with degassed distilled water 0.3 ml/min recorded esophageal body peristalsis Infusion port (Midesophagus) perfused with degassed distilled water at 0.45 ml/min recorded intragastric pressure 17 18

4 Pressures external transducers with output to a computerized acquisition system Vertical perfusion baseline offset any hydrostatic pressure gradient among perfusion side holes at different height Esophageal ph an antimony electrode Combined measurement of esophageal pressures and ph were synchronized by a digital data logger The data were digitized and displayed commercially available software After overnight fast subjects were studied in an upright position The position and length of LOS the station pull-through technique at 1-cm intervals the sleeve sensor was positioned across the LOS The ph electrode was affixed to the manometric assembly 10 water swallows of 5 ml each 10-minute test primary peristalsis of esophageal body and LOS relaxation 5, 20-mL boluses of air injected (1 second) 1 hour TLOSR at fasting state Test Secondary peristalsis esophageal distention given a standard soft mixed nutrient test meal (400 kcal, 55% fat) 2 hour 24-hour ambulatory monitoring postprandial ph and manometric studies Data Analysis Both fasting and 2-hour postprandial data a single investigator End expiratory basal LOS pressure was referenced to end expiratory intragastric pressure 1-minute intervals over a 10-minute period 23 24

5 amplitude >10 mmhg amplitude >30 mmhg TLOSRs end-expiratory esophageal pressure GOPG end-expiratory intragastric pressure Gastric baseline pressure Normal swallow-induced lower esophageal sphincter relaxation Statistical Analyses Mean ( ± SEM) Compared using 1-way (ANOVA) linear regression analysis Multiple regression analysis Acid reflux Slow downward drift Pearson correlation coefficients and regression coefficients P value < 0.05 statistically significant 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 (71) 3 (10.7) 4 (14.1).69 a Obstructive sleep apnea 0 (0) 0 (0) 6 (21.4).002 a (%) 29 Table 1. Comparison of Demographics, Anthropometric Measurements, and Fasting Motility Parameters Among 3 Groups Control Overweight Obese P value 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 (5.9) (16.1) <.001 LOS length, cm (SE) 3.4 (0.7) 3.8 (0.6) 3.6 (0.5).69 a LOS pressure, mm Hg (SE) 16.9 (2.8) 17.3 (2.9) 16.3 (3.1).57 Total number of TLOSR in (0.2) 0.9 (0.3) 1.0 (0.3) 34 hour 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 χ 2 test. 30

6 P <.001 P <.001 Figure1 (B)gastroesophageal pressure gradient (GOPG) The error bars denote mean ± 2 SEM. Figure1 (A) total number of TLOSR in 2 hours 31 Postprandial GOPG correlated significantly with total number of TLOSR (r =0.83, P <.001) and TLOSR with reflux (r= 0.84 P < 0.01). 32 Table 2. Comparison of Postprandial TLOSR, GOPG, and 24-Hour Esophageal Acid Exposure Among 3 Groups Control Overweight Obese No Total number of TLOSR in 2 hours Total number of TLOSR with acid reflux in2 hours Proportion of TLOSR with acid reflux in 2 hours (%) P value 2.1 (1.2) 3.8 (1.6) 7.5 (2.0) < (0.6) 2.0 (1.1) 4.5 (1.8) < (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 r = 0.81, P <.001 Total % time ph 0.2 (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 0.4 (0.3) 1.4 (0.7) 4.5 (0.7) <.001 ph NOTE. Data expressed as mean (SEM). Post hoc analysis using Bonferroni s method: a P =.15for overweight vs obese group; b P = for control vs overweight group; P <.001 for other post hoc analyses. Figure 2. (A) The correlation between body mass index and total number of TLOSR in 2 hours 34 r = 0.88, P <.001 r = 0.84, P <.001 Figure 2. (B) number of TLOSR with acid reflux in 2 hours. 35 Figure 3. (A) The correlation between waist circumference and total number of TLOSR in 2 hours 36

7 r = 0.89, P <.001 Obesity has been implicated as a major risk factor of GERD An association between obesity, hiatus hernia, and various motility dysfunctions of the upper gastrointestinal tract in GERD patients Figure 3. (B) The correlation between waist circumference and number of TLOSR with acid reflux in 2 hours. 37 Obesity predisposes to these conditions or whether they merely coexist in GERD 38 Obesity was associated TLOSR Postprandial gastroesophageal reflux and esophageal acid exposure The frequency of TLOSR was strongly correlated with both BMI and waist circumference 39 Rates of TLOSR were substantially higher in overweight and obese subjects during the postprandial period 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 40 Argues against a major difference in the rate of TLOSRs between normal subjects and patients with GERD Not stratified for BMI Gastric distention is a major mechanism of postprandial TLOSRs obese patients tend to overeat a more distended proximal stomach postprandial TLOSR 41 Rate of TLOSR could not be explained by excessive calorie intake, over distention of stomach, or hypersensitivity of gastric mechanical stretch receptors Obstructive sleep apnea may be associated with GERD Orr WC, et. al., 2004 No association between obstructive sleep apnea and TLOSR obstructive sleep apnea may be an epiphenomenon in the relationship between obesity and GERD 42

8 Mechanisms Postprandial TLOSR and GOR in obese subject Intragastric pressure The significant correlation between TLOSR with GOPG, BMI, and waist circumference in a dose-effect relationship 43 Pandolfino et al High-resolution solid-state manometry Significant correlation between intragastric pressure and GOPG with BMI and waist circumference TLOSR is a neurally mediated reflex mechanical distention of the proximal stomach. Holloway RH, et. al and Kahrilas PJ, et. al., Both stretch and tension mechanoreceptors at the proximal stomach have been implicated to play an important role in TLOSR Stretch receptors seem to be more relevant Penagini R, et al Intragastric pressure may also be the culprit of proportion of TLOSR with acid reflux observed in obese and overweight subjects Stepwise pressure-controlled barostat distention of the proximal stomach provokes TLOSR, which is strongly correlated with intragastric pressure Scheffer RC, et al Not gastric volume is greater in TLOSRs associated with acid gastroesophageal reflux Scheffer RC, et al Postprandial intragastric pressure Stimulation on both stretch and tension mechanoreceptors in the proximal stomach Postprandial TLOSRs in abdominal obesity Pressure gradient between the stomach and the esophagus Proportion of TLOSR with acid reflux 47 Issues Status of nonacidic and air reflux in aggravated postprandial TLOSR related to obesity impedance monitoring Weight reduction can reverse these early functional changes of the LOS before irreversible disruption of the GOJ integrity Availability of unbuffered acidic gastric content at the GOJ has been reported 48

9 Further studies To evaluate the role of abdominal obesity and increased intragastric pressure in topographic distribution of gastric acid in causing GERD Conclusion Obesity is associated with excessive TLOSR during the postprandial period, which results in elevated esophageal acid exposure in subjects without GERD Abnormal postprandial LOS function may be an early event in the pathogenesis of obesity-related GERD Hiatus hernia Erosive esophagitis Achalasia 53 54