Symptoms of gastroesophageal reflux disease (GERD) are. Effects of Age on the Gastroesophageal Junction, Esophageal Motility, and Reflux Disease

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5: Effects of Age on the Gastroesophageal Junction, Esophageal Motility, and Reflux Disease JACQUELINE LEE,* ANGELA ANGGIANSAH, ROY ANGGIANSAH, ALASDAIR YOUNG,* TERRY WONG,* and MARK FOX*, *Department of Gastroenterology and Esophageal Laboratory, Guy s and St. Thomas NHS Foundation Trust, London, United Kingdom See Schey R et al on page 1787 for companion article in the December 2007 issue of Gastroenterology. Background & Aims: The prevalence of complicated gastroesophageal reflux disease (GERD) increases with age; however, the mechanism by which this occurs is uncertain. This study assessed (1) whether physiologic degradation of the gastroesophageal junction and esophageal motility occurs with aging, and (2) whether these effects are associated with increased esophageal acid exposure and reflux symptoms in the elderly. Methods: Retrospective study of 1307 patients referred for investigations of reflux symptoms (median age, 49 years; range, years) was conducted. Manometry assessed LES pressure, LES length, and esophageal peristalsis. Ambulatory ph studies assessed esophageal acid exposure (% time ph <4) during a period of 24 hours; reflux symptoms were assessed by validated questionnaire. Results: On multivariate regression, esophageal acid exposure was associated independently with decreasing LES pressure (P <.0001) and abdominal LES length (P <.0004). Dysmotility exacerbated reflux in the recumbent position (P <.004). Acid exposure increased with age (P <.0001), a 1.1%/24 hours (95% confidence interval, 0.4% 1.4%) increase in acid exposure every decade (more pronounced in the recumbent position). The age-related increase in acid exposure was associated independently with decreasing abdominal LES length (P <.001) and increasing dysmotility (P < 0.01). Reflux symptoms increased with acid exposure (P <.001); however, at any given level of exposure, symptom severity was less in the elderly (P <.006). Conclusions: Age was associated with an increase in esophageal acid exposure; however, the severity of reflux symptoms reduced with age. These changes were associated with progressive decrease in abdominal LES length and esophageal motility. Increasing GERD severity in the elderly is related to degradation of the gastroesophageal junction and impaired esophageal clearance. Symptoms of gastroesophageal reflux disease (GERD) are common in the community and have important, adverse effects on patient health and quality of life. 1 The prevalence and severity of GERD increase with age, 2 5 and a long history of reflux symptoms is associated with increased risk of esophageal adenocarcinoma. 6 These concerns highlight the importance of identifying and treating the underlying causes of GERD in the elderly population. The gastroesophageal junction (GEJ) forms a barrier against reflux of gastric contents. Early investigations demonstrated that the effectiveness of the reflux barrier depended on LES pressure and length, especially the segment of the LES exposed to intra-abdominal pressure. 7 The perfused LES sleeve revealed that most reflux events occur during transient LES relaxations (TLESRs). 8,9 Notwithstanding this fact, the frequency, duration, and completeness of TLESRs are not elevated in most patients; rather, it is the risk of reflux during such events that is increased in GERD These findings indicate that factors other than GEJ function determine the risk of acid reflux during TLESRs In support of this hypothesis, mechanistic studies of the GEJ have documented progressive structural degradation of the reflux barrier, comparing healthy controls with GERD patients with an intact reflux barrier and those with hiatus hernia. 16 Moreover, in patients with GERD, frequent, intermittent spatial separations of the extrinsic (diaphragmatic crura) and intrinsic (LES) components of the GEJ (i.e, intermittent formation of a hiatus hernia) are associated with an increase in reflux. 17 Together these findings suggest that although most reflux events occur during functional relaxation (or weakness) of the GEJ, it is the structural changes at the reflux barrier that lead to increased frequency of reflux episodes and acid exposure in GERD. It is well-known that the prevalence of hiatus hernia and severe GERD is higher in the elderly 2 5 ; however, only a minority of GERD patients have an overt hiatus hernia, and it has not been established whether degradation of the reflux barrier is the mechanism by which the severity of GERD increases with age. In addition to the role of the reflux barrier, there has been interest in the role of esophageal motor and sensory function in GERD, especially since the introduction of multichannel, intraluminal impedance (MII). Ineffective esophageal motility and clearance are important because prolonged exposure to acid and other noxious substances in gastric refluxate (eg, bile acid, pepsin) increase the risk of reflux esophagitis, peptic stricture, and, potentially, adenocarcinoma. 18,19 Esophageal sensitivity is also relevant in the pathophysiology and presentation of GERD. Increased acid sensitivity exacerbates symptoms related to acid and nonacid re- Abbreviations used in this paper: CI, confidence interval; GEJ, gastroesophageal junction; GERD, gastroesophageal reflux disease; MII, multichannel, intraluminal impedance; PPI, proton pump inhibitor; TLESR, transient lower esophageal sphincter relaxation by the AGA Institute /07/$32.00 doi: /j.cgh

2 December 2007 AGE, ESOPHAGEAL FUNCTION, AND ACID EXPOSURE 1393 flux, whereas decreased acid sensitivity might compromise esophageal clearance by reducing the swallowing response to reflux. These issues are also of particular relevance in the elderly community, in whom the prevalence of esophageal dysfunction and the complications of GERD are common. 20 This study assessed (1) whether progressive physiologic degradation of the reflux barrier and esophageal dysfunction are associated with increasing age, and (2) whether these changes explain the increased severity of reflux disease reported in the elderly population. To address these issues we analyzed a large cohort of patients with reflux symptoms referred for esophageal manometry and 24-hour ambulatory ph studies. Methods Patients Patients with typical reflux symptoms referred for esophageal manometry and 24-hour ambulatory ph studies during a 4-year period from November 2000 October 2004 were eligible for inclusion. The severity of symptoms was assessed by a standardized questionnaire. 21 Exclusion criteria comprised (1) predominance of atypical symptoms (eg, abdominal pain, chronic cough), (2) use of acid-suppressive medication within 1 week of evaluation, (3) previous esophageal or gastric surgery, (4) comorbid conditions that might interfere with esophageal or gastric motility (eg, systemic sclerosis), and (5) use of medications that might affect saliva production or gastrointestinal function. Patients were studied in a single esophageal laboratory at a tertiary referral unit providing physiologic investigations for hospitals serving a community of 6 million. The endoscopic report was not routinely included in the referral letter, and even when present, endoscopy had rarely been performed in proton pump inhibitor (PPI) naïve patients. Thus the severity of mucosal disease was not included in the analysis. All patients provided written consent before undergoing study procedures. The acquisition of patient demographic and questionnaire data was approved by the ethics committee of St Thomas Hospital. Esophageal Manometry and Ambulatory Esophageal ph Monitoring Determination of resting LES properties and esophageal body motility was performed by using a 6-pressure sensor solid state manometric assembly to record gastric and esophageal pressures (Gaeltec Ltd, Isle of Skye, UK). The catheter was advanced transnasally into the stomach; the LES position and the pressure inversion point were determined during a station pull-through procedure with at least 3 respiratory cycles in each position. Physiologic measurements included total and abdominal LES length, with the abdominal LES defined by the position of the pressure inversion point. The presence of a hiatus hernia was defined by the absence of an abdominal LES. The distance between the LES and pressure inversion point described the size of the hiatus hernia (negative abdominal LES length). LES pressure relative to intragastric reference was measured and peristaltic function and deglutitory LES relaxation were assessed by ten 5-mL water swallows separated by at least 30 seconds and classified by the investigator as normal or ineffective: failed (no peristalsis in the distal esophagus), simultaneous (contraction onset velocity 6 cm/s), or hypotensive (contractile pressure 30 mm Hg 5 cm above the LES). Ambulatory esophageal ph studies were performed by using a catheter with a single antimony electrode (Medtronic Synectics, Shoreview, MN). Calibration was performed before and after the study with reference solutions of ph 1 and 7. Data were stored in a solid-state memory unit worn by the subject (Mark III Digitrapper; Medtronic Synectics). The ph electrode was placed 5 cm proximal to the superior aspect of the manometrically determined LES. After catheter placement, subjects were encouraged to pursue their usual activities and diets. Data were analyzed with Gastrosoft Software (Medtronic Synectics). The primary outcome measure of 24-hour ph measurement was esophageal acid exposure (percentage of time ph 4/24 h), the single most reproducible and robust diagnostic marker of GERD. 22,23 Further measurements derived from ph studies (eg, number of reflux episodes) were not included in the analysis to avoid problems related to multiple comparisons. Statistics The results of manometry and ph studies were acquired and analyzed separately before independent entry into the database. Results are expressed as mean and standard deviation or median and interquartile range as appropriate for parametric and nonparametric data. Univariate regression assessed whether demographic or physiologic variables covaried with measurements of esophageal acid exposure. Unpaired t tests or Mann- Whitney U tests were performed where a continuous relationship between variables was not present (eg, hiatus hernia vs no hiatus hernia) and to investigate variation within the observed range. Parameters significant according to the univariate analysis were included in a multivariate logistic regression. Independent significant factors were identified with an ascending selection procedure. The F statistic (analysis of variance) expressed the goodness of fit of a regression model to the random variable. The t statistic expresses the significance of a variable s contribution to a regression model. Sensitivity analysis assessed the magnitude (and 95% confidence intervals [CIs]) of the effect of age and physiologic variables on esophageal acid exposure (ie, clinical relevance). Statistical significance was set at.05 after Bonferroni correction for multiple comparisons. Ten variables were included in the multivariate regression; thus individual comparisons were significant at.005 or better (0.05/10). All calculations were performed by GraphPad Prism v4 and InStat v3 (GraphPad, San Diego, CA). Results Baseline Characteristics Three thousand two hundred fifty consecutive patients were referred for esophageal investigations during the 4-year study period, of whom 1307 (40.1%) had typical reflux symptoms and were eligible for inclusion. Of these, 74 patients (5.6%) did not tolerate the nasoesophageal catheter, or measurement failed for technical reasons. Data were collected from 1232 patients, and 985 (80.0%) patients with complete demographic and physiologic data were included in the analysis. The mean age of the study group was years (range, years), with a significant male predominance (male, 58%; female, 42%; P.01). The age distribution was parametric, with n 99 aged 30 years, n 255 aged 30 39, n 299 aged 40 49, n 313 aged 50 59, n 205 aged 60 69, and n 96 aged 70 years. The interaction between age, sex, reflux symp-

3 1394 LEE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 12 Figure 1. Increasing esophageal acid exposure was associated with a progressive, continuous decrease in LES pressure and abdominal LES length across the observed range. Both associations were significant (P.0001); however, the impact of structural degredation of the reflux barrier (ie, decreasing abdominal LES length) was more pronounced than that of functional weakness (ie, decreasing LES pressure). toms, and esophageal acid exposure was studied in 407 eligible patients who underwent the study procedures and completed the symptom questionnaire. 21 There was no difference in baseline characteristics between patients with and without symptom data included in the multivariate analysis (n 985) and those excluded as a result of incomplete data. Univariate Analysis Effect of lower esophageal sphincter pressure and length on acid exposure. There was a highly significant correlation between LES pressure and esophageal acid exposure during a period of 24 hours (F 180, P.0001) that was consistent in both positions. There was also a highly significant correlation (F 74, P.0001) between abdominal LES length and esophageal acid exposure (Figure 1). An effect was also found for total LES length; however, this was less pronounced (F 24, P.001). There was no categorical change in acid exposure between patients with and without a hiatus hernia; rather, the changes were continuous across the observed range (Figure 1). Effect of esophageal motility on acid exposure. There was a highly significant correlation between esophageal dysmotility and esophageal acid exposure (F 120, P.0001). This effect was present in the recumbent position (F 110, P.0001) and also in the upright position (F 58, P.0001). The effect of esophageal dysmotility on acid exposure was most pronounced in the recumbent position in patients with the most severe dysmotility (Figure 2). In particular, the frequency of failed ( nontransmitted ) peristalsis was associated with esophageal acid exposure in the recumbent position during the ph study (P.001). There was an association between the frequency of synchronous contraction (P.03) but not hypotensive contractions 30 mm Hg (P NS) with acid exposure. Figure 2. Increasing esophageal acid exposure was observed with increasing frequency of ineffective esophageal motility in each position on univariate analysis. The effect of esophageal dysmotility on GERD was significant only in the recumbent position on multivariate regression.

4 December 2007 AGE, ESOPHAGEAL FUNCTION, AND ACID EXPOSURE 1395 Multivariate Analysis Total twenty-four hour esophageal acid exposure. The multivariate logistic regression identified only 2 physiologic variables with independent effects on 24-hour esophageal acid exposure, LES pressure (t 6.0, P.0001) and abdominal LES length (t 3.6, P.0004). Acid exposure increased 0.3% for every 1 mm Hg decrease in LES pressure (95% CI, 0.2% 0.4%) and 1.0% for every 10-mm decrease in abdominal LES length (95% CI, 0.6% 1.4%). Total LES length was not independently associated with ph measurements when abdominal LES length was included in the multivariate regression. Ineffective esophageal motility was not associated with 24-hour esophageal acid exposure (t 1.5, P.13). The effect of LES pressure and abdominal LES length on the results of 24-hour ph studies was highly significant; however, the model explained only a proportion of variability in esophageal acid exposure (F 28.5, P.0001 with r 0.33). Esophageal acid exposure and position. Three independent variables associated with esophageal acid exposure in the recumbent position including LES pressure (t 4.2, P.001), abdominal LES length (t 3.2, P.002), and ineffective esophageal motility (t 2.9, P.004). In the upright position only LES pressure (t 4.2, P.001) was independently associated with % time ph 4 esophageal acid exposure, although the association of abdominal LES length with acid exposure approached significance (t 3.2, P.08). There was no relation between ineffective esophageal motility and acid exposure (P NS). Interaction between physiologic variables. In the multivariate analysis, LES pressure, abdominal LES length, and ineffective esophageal motility had significant effects on esophageal acid exposure; thus each contributed to reflux protection in an independent manner. However, these factors form an integrated biologic system, and it is necessary to understand the extent to which GEJ structure and function and esophageal motility relate to each other. Abdominal LES length (but not overall LES length) was associated with LES pressure (P.0001) and esophageal motility (P.002). Patients with a hiatus hernia had lower LES pressure ( vs mm Hg, P.001) and more frequent ineffective esophageal motility (58% 35.0% vs 32% 33.0%, P.02); however, there was no categorical change in esophageal physiology between patients with and without a hiatus hernia; rather, as the length of the intra-abdominal LES became shorter (or hiatus hernia size increased), there was a progressive fall in LES pressure and rise in the prevalence of ineffective esophageal motility. Effect of Age on Esophageal Physiology and Acid Exposure Having identified the physiologic measurements that were significantly associated with esophageal acid exposure, a separate analysis was performed to assess whether these factors were responsible for any change in reflux severity with aging. Increasing age was associated with increasing percentage 24- hour esophageal acid exposure (F 46, P.0001), with an increase of 1.1% time esophageal ph 4/24 h (95% CI, 0.6% 1.4%) for every additional decade (Figure 3A). The percentage increase in the recumbent (1.2%/decade; 95% CI, 0.4% 2%) was twice as large as in the upright position (0.6%/decade; 95% CI, 0.4% 1.1%). On multivariate regression, increasing age was associated with decreasing abdominal LES length (F 35, P Figure 3. (A) Increasing age was independently associated with increasing esophageal acid exposure in patients with reflux symptoms referred for investigation. In a separate analysis the age-related increase in esophageal acid exposure was associated with (B) progressive decrease in abdominal LES length and (C) progressive impairment of esophageal motility. These effects were robust to outliers, and group comparisons confirmed that the prevalence of ineffective motility was highest in the elderly group..001) and increasing prevalence of ineffective esophageal motility (F 14, P.001). These findings are illustrated by the progressive increase in esophageal acid exposure and change in esophageal physiology seen across the observed age range (Figure 3B, C). No independent effects of age on LES pressure or total LES length were present. Group comparisons between the most elderly group ( 70 years, n 96) and other patients with reflux symptoms ( 70 years, n 889) revealed a higher prevalence of hiatus hernia (34% vs 18%, P.01) and ineffective motility (53% vs 38%, P.001).

5 1396 LEE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 12 Figure 4. The interaction of age, sex, and GERD. Esophageal acid exposure increased with age and was significantly higher in male patients referred for investigation (both P.0001). In contrast, patient reports of reflux symptoms did not increase with age; rather, a small but significant decrease was observed (P.006). Female patients reported slightly more reflux symptoms independent of esophageal acid exposure (P.03). A separate analysis in patients with normal esophageal acid exposure (n 91) found no significant changes in esophageal motility or LES function, with aging independent of the presence of reflux disease, except for a reduction in contractile pressure (54 24 vs mm Hg, P.04) without an increase in ineffective motility as defined in the methods. Reflux symptom scores increased with esophageal acid exposure (0.16/percent acid exposure; 95% CI, ; P.001); however, there was an important interaction with age such that the severity of reflux symptoms was not greater in the elderly, despite higher percentage time esophageal acid exposure. On the contrary, at any given level of esophageal acid exposure, the severity of reflux symptoms reduced with age ( 0.3/decade; 95% CI, ; P.006) (Figure 4). The contribution of esophageal acid exposure in the upright and supine position to symptom severity was found to be somewhat higher in the upright (t 4.3, P.0001) than supine position (t 2.9, P.004); however, the comparison of trends failed to reach significance (P.13). Male patients referred for the investigation of reflux symptoms had, on average, higher esophageal acid exposure than female patients (12.3% 9.6% vs 9.5% 9.1% time ph 4/24 h; P.0001). Abdominal LES length was significantly shorter in men than women ( cm vs cm; P.001), and the prevalence of ineffective esophageal motility was higher (54% 35% vs 38% 30%; P.01); however, gender had no effect on LES pressure ( vs mm Hg; P.1). Female patients reported slightly (but significantly) more reflux symptoms independent of acid exposure (0.84 higher compared with men (95% CI, ; P.03) (Figure 4). Discussion This study describes the effects of aging on esophageal physiology and GERD in a large population of patients with reflux symptoms. The median age of 985 patients included in the analysis was 49 years with a wide age distribution, including nearly 100 patients aged older than 70 years. The results document a significant increase in esophageal acid exposure with age; however, this was not matched by an increase in reflux symptoms. Multivariate regression and group comparisons revealed that this process was associated with progressive structural degradation of the GEJ (ie, reduction in the abdominal LES length) and esophageal peristaltic dysfunction, effects that explain in part the increased prevalence of complicated reflux disease in the elderly population. This study confirms that the structure and function of the GEJ are both crucial to the reflux barrier; LES pressure and the abdominal LES length were both independently associated with esophageal acid exposure. Importantly, the relationships were continuous. No cutoff value could be identified below which LES pressure or abdominal LES length was abnormal (Figure 1). Thus, there was no step change in acid exposure between patients with and without a hiatus hernia; rather, decreasing abdominal LES length was associated with a progressive increase of acid esposure across the observed range. Variation in abdominal LES length had more pronounced effects than LES pressure or motility on esophageal acid exposure (Figure 1); however, there was an important interaction with position. This was expected and reflects the likely different mechanism of reflux in the 2 situations (not measured directly in this study). In the upright position the dominant mechanism of reflux is TLESR. 8,9 In the supine position TLESRs are suppressed, and reflux rarely occurs unless the GEJ barrier is very weak or structurally incompetent. 24,25 When reflux occurs, voluntary swallowing with primary peristalsis is the main mechanism that clears the esophagus. 26 If reflux occurs when the patient is asleep, swallowing might not occur. Moreover, whereas gravity aids clearance in the upright position, effective motility is required when supine (Figure 2). 27 Having identified physiologic measurements that were associated with esophageal acid exposure, a separate analysis was performed to assess whether these changes explained the increase in esophageal acid exposure found in the elderly population. Overall, a 1.1% (95% CI, 0.6% 1.4%) increase in esophageal acid exposure was observed with each decade (Figure 3A). Increased GERD severity with age was correlated with a progressive reduction in abdominal LES length and an increase of ineffective esophageal motility (Figure 3B, C); however, no independent effect of LES pressure was observed. Group comparisons emphasized the importance of these mechanisms in the most elderly patients ( 70 years) tested. Consistent with these findings, the effects of age on esophageal acid exposure were most marked in the recumbent position. This provides consistent support for the idea that progressive structural degradation of the reflux barrier is the single most important cause of increasing prevalence and severity of GERD in the elderly population (ie, reduction in the abdominal LES segment as opposed to LES pressure). In addition, increasing esophageal dysmotility exacerbates acid exposure with increasing age, especially in the recumbent position. In the absence of longitudinal studies, it is not possible to know whether these changes are the cause or the effect of GERD. Evidence has been advanced for both positions. This study found no significant changes in esophageal motility or LES function with aging independent of the presence of reflux disease, except for a small

6 December 2007 AGE, ESOPHAGEAL FUNCTION, AND ACID EXPOSURE 1397 reduction in contractile pressure without an increase in ineffective motility. This provides some support for the presence of a genetic predisposition to GERD that might predispose to age-related structural changes at the GEJ 21 and loss of cholinergic neurons from the submucosal and myenteric plexus that impairs esophageal function. 28 Conversely, inflammatory cytokines produced by reflux esophagitis inhibit esophageal motility, 29 and acid damage could produce scarring and esophageal shortening, drawing the intrinsic LES into the thoracic cavity. 30 These 2 processes are not mutually exclusive and could result in a vicious cycle of acid damage and progressive structural degredation of the reflux barrier. Questionnaire data in 407 patients revealed further information about GERD in the elderly. As expected, the severity of reflux symptoms increased with esophageal acid exposure; however, the severity of reflux symptoms was not greater in the elderly, despite higher esophageal acid exposure. Indeed, at any given level of esophageal acid exposure, the severity of reflux symptoms reduced with age (Figure 4). This result is consistent with a large post hoc analysis of baseline data pooled from 5 prospective, randomized, controlled clinical trials of PPI treatment in GERD. 31 This study reported increased prevalence of severe esophagitis with age but no indication that this was linked to increased symptom severity. 31 Indeed, although acid reflux and the complications of GERD are more prevalent in the elderly, most publications (including one longitudinal study with 17 years of follow-up) report that symptom severity remains either constant or diminishes with time. 2 5,32 Because symptom severity did not increase with esophageal acid exposure and age, referral bias is unlikely. Nevertheless, some risk of bias remains because the effect of aging on reflux was more pronounced in the supine than the upright position. Reflux is less likely to be perceived in the supine, sleeping individual, and there was some evidence that this resulted in under-reporting of symptom severity relative to GERD severity in the elderly. Although reporting bias and a reduced willingness to seek medical care in old age cannot be excluded, growing evidence suggests that older individuals are less likely to report severe reflux symptoms as a result of decreased visceral sensitivity, 33,34 possibly as a result of loss of afferent nerves. 28 Decreased esophageal sensitivity might also exacerbate acid damage by reducing the stimulus for voluntary swallowing and delaying reflux clearance. The lack of normal volunteers from across a wide age range is a limitation of this and many other reflux studies. Here, patients with symptoms but without pathologic esophageal acid exposure might provide a relevant group for comparison because no important changes in esophageal motility or LES function with aging were found independent of GERD. Moreover, the physiologic measurements in this group were similar to asymptomatic individuals without reflux disease in previous studies from our laboratory. 21 The presence of mucosal disease was not included in the analysis; however, the presence of esophagitis is an unreliable measure of GERD severity because of the widespread use of empiric PPI treatment in this population. Invasive, time-consuming investigations used in mechanistic studies document a direct cause and effect link between physiologic events and reflux; however, this is not practical in large-scale clinical studies. Despite the limitations of conventional manometry for the assessment of the GEJ and motility, 35,36 standard pull-through measurements do reflect underlying pathophysiology. For example, LES pressure correlates with GEJ compliance assessed by barostat, 16 and the overlap between the intrinsic and diaphragmatic LES on stationary pull-through (ie, abdominal LES length) is a marker of GEJ instability on high-resolution manometry (Fox et al, unpublished observations). Moreover, analysis of a large number of patients in the current study reduces variation and provides sufficient statistical power to assess whether these factors affect esophageal acid exposure. Thus conventional, stationary manometry provides surrogate measurements that can be used to test hypotheses based on more detailed mechanistic studies (if large numbers are studied). This statement is supported by the highly significant associations between age, esophageal physiology, and acid exposure reported, although measurement technique might also explain why only a modest proportion of variability in acid exposure was explained by the regression model (r 0.33). In addition, this is likely because factors such as diet, 37 salivation, 38 gastric acid production, and gastric emptying 39 were not assessed. The aim of esophageal investigations is to document and understand the physiologic basis of esophageal symptoms and disease and to guide rational treatment. Current guidelines do not recommend manometry and ph studies in patients with typical reflux symptoms because findings do not affect first-line management. 1 However, as more patients are prescribed empiric PPIs, there is increasing awareness that not all patients (and not all symptoms) respond to medical management. Studies with combined ph and MII have shown that nonacid reflux is a frequent cause of persistent symptoms in patients on treatment. 40 It can be speculated that elderly patients with persistent symptoms in whom the structure of the reflux barrier is disrupted or unstable should be considered for physical antireflux procedures (eg, fundoplication), whereas those with unstable LES function should be treated with medications that suppress transient LES relaxation (eg, baclofen). Surgical antireflux procedures might not be ideal in this patient group, and endoscopic antireflux procedures might not be ready for routine clinical practice 1 ; however, this study suggests that treatment aimed at correcting structural degradation of the reflux barrier could be valuable in halting the progressive increase in GERD severity that occurs with increasing age. References 1. Fox M, Forgacs I. Gastro-oesophageal reflux disease. BMJ 2006; 332: El-Serag HB. 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7 1398 LEE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 12 mechanism for postprandial gastroesophageal reflux. Gastroenterology 1985;89: McNally E, Kelly J, Ingelfinger F. Mechanism of belching: effect of gastric distention with air. Gastroenterology 1964;46: Bredenoord AJ, Weusten BL, Timmer R, et al. Gastro-oesophageal reflux of liquids and gas during transient lower oesophageal sphincter relaxations. Neurogastroenterol Mot 2006;18: Trudgill NJ, Riley SA. Transient lower esophageal sphincter relaxations are no more frequent in patients with gastroesophageal reflux disease than in asymptomatic volunteers. Am J Gastroenterol 2001;96: Iwakiri K, Hayashi Y, Kotoyori M, et al. Transient lower esophageal sphincter relaxations (TLESRs) are the major mechanism of gastroesophageal reflux but are not the cause of reflux disease. Dig Dis Sci 2005;50: Bredenoord AJ, Weusten BL, Curvers WL, et al. Determinants of perception of heartburn and regurgitation. 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Am J Gastroenterol 1997;92: Lasch H, Castell DO, Castell JA. Evidence for diminished visceral pain with aging: studies using graded intraesophageal balloon distension. Am J Physiol 1997;272:G1 G Fass R, Pulliam G, Johnson C, et al. Symptom severity and oesophageal chemosensitivity to acid in older and young patients with gastro-oesophageal reflux. Age Ageing 2000;29: Agrawal A, Tutuian R, Hila A, et al. Identification of hiatal hernia by esophageal manometry: is it reliable? Dis Esophagus 2005; 18: Fox M, Hebbard G, Janiak P, et al. High-resolution manometry predicts the success of oesophageal bolus transport and identifies clinically important abnormalities not detected by conventional manometry. Neurogastroenterol Motil 2004;16: Fox M, Barr C, Nolan S, et al. The effects of dietary fat and calorie density on esophageal acid exposure and reflux symptoms. Clin Gastroenterol Hepatol 2007;5: Helm JF, Dodds WJ, Pelc LR, et al. Effect of esophageal emptying and saliva on clearance of acid from the esophagus. N Engl J Med 1984;310: Grossi L, Ciccaglione AF, Travaglini N, et al. Swallows, oesophageal and gastric motility in normal subjects and in patients with gastro-oesophageal reflux disease: a 24-h ph-manometric study. Neurogastroenterol Motil 1998;10: Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-ph monitoring. Gut 2006;55: Address requests for reprints to: Mark Fox, MD, Department of Gastroenterology, University Hospital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland. dr.mark.fox@gmail.com; fax: Supported by Guys and St. Thomas NHS Trust.