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Background & Aims: Esophageal acid exposure is higher in gastroesophageal reflux disease (GERD) patients with hiatus hernia than in those without. We investigated the effect of a sliding hiatus hernia on the mechanisms underlying spontaneous gastroesophageal reflux over 24 hours. Methods: Twelve GERD patients with and 10 GERD patients without hiatus hernia were studied for 24 hours. Combined esophageal pH and manometric recordings of the pharynx, lower esophageal sphincter (LES), and stomach were performed using a multiple-lumen assembly incorporating a Dent sleeve connected to a portable water-perfused manometric system and a pH glass electrode. Results: Patients with hiatus hernia had greater esophageal acid exposure (7.6% vs. 3.3%; P < 0.01) and more reflux episodes (3.1 vs. 1.8/h; P < 0.001) than those without. LES pressure, the incidence of transient LES relaxations (TLESRs), and the proportion of TLESRs associated with acid reflux were comparable in both groups. Both groups had equal numbers of reflux episodes associated with TLESRs and swallow-associated prolonged LES relaxations. Patients with hiatus hernia had more reflux associated with low LES pressure, swallow-associated normal LES relaxations, and straining during periods with low LES pressure. Conclusions: The excess reflux in GERD patients with hiatus hernia compared with those without is caused by malfunction of the gastroesophageal barrier during low LES pressure, swallow-associated normal LES relaxations, deep inspiration, and straining.
Studies on the mechanisms underlying gastroesophageal reflux in healthy volunteers showed that 80%–100% of the gastroesophageal reflux episodes are associated with transient lower esophageal sphincter relaxations (TLESRs).
Several studies showed that TLESRs are also the most important mechanism of acid reflux in patients with gastroesophageal reflux disease (GERD), in whom approximately 70% of the reflux episodes are related to TLESRs. Other mechanisms such as low lower esophageal sphincter (LES) pressure, abdominal straining, deep inspiration, and normal swallow-associated LES relaxations account for the remaining 30% of the reflux episodes in patients with GERD.
Hiatus hernia is seen more frequently in patients with esophagitis than in subjects without esophagitis, and several studies report a correlation between hiatus hernia and the severity of the esophagitis.
Fluoroscopic studies and studies in which reflux was provoked by the Valsalva and Müller maneuvers, leg raising, and coughing suggest that the presence of hiatus hernia increases susceptibility to reflux events associated with normal swallow-associated relaxations and straining.
However, to date no studies have investigated the mechanisms underlying spontaneous gastroesophageal reflux in patients with hiatus hernia over 24 hours. In particular, the question of whether the excess reflux found in patients with hiatus hernia is caused by a higher incidence of TLESRs has remained unexplored. Therefore, the aim of this study was to investigate the effect of a sliding hiatus hernia on the mechanisms of gastroesophageal reflux during 24 hours.
Subjects and methods
Twenty-two patients with GERD and a history of recurrent heartburn for at least 3 months participated in the study. To be included in the study, patients had to have symptoms of heartburn interfering with concentration and/or daily activities for at least 3 of 7 days as documented in a diary during a 1-week period before enrollment. Upper endoscopy was performed within 4 weeks before the study to assess whether hiatus hernia was present (gastroesophageal junction at 3 cm or more above the diaphragmatic impression) and to determine the severity of esophagitis.
Twelve patients had a sliding hiatus hernia (11 men and 1 woman; mean age 47.9 years; range, 32–59 years). The median length of the hiatus hernia was 3 cm (range, 3–6 cm). Esophagitis grade 0, 1, and 2 (according to the modified Savary–Miller scale) was observed in 2, 6, and 4 of these patients, respectively. No hiatus hernia was found in the remaining 10 GERD patients (4 men and 6 women; mean age, 39.8 years; range, 21–53 years). Six of these patients had no esophageal erosions, and the other 4 had grade 1 esophagitis. All patients without esophageal erosions had symptoms related to esophageal acid exposure, as demonstrated by 24-hour pH measurement (symptom association probability score >95% and symptom index >50%).
The use of antisecretory drugs was discontinued at least 5 weeks before upper endoscopy. None of the patients used drugs known to influence esophageal or gastric motility or had any disease or underwent any surgical procedures that might affect gastric acid secretion or gastroesophageal motility. Stationary esophageal manometry performed within 4 weeks before the study did not show an esophageal motility disorder other than GERD-related dysmotility in any of the subjects.
After an overnight fast, the esophageal pH and manometric catheters were inserted through the nose. Hereafter the assemblies were positioned as described below. At 7:30 AM, the study was started. At fixed times, standardized meals were taken (breakfast, 42.2 g carbohydrate, 27.8 g protein, 20.8 g fat, 458 kcal; lunch, 94.8 g carbohydrate, 30 g protein, 37.2 g fat, 870 kcal; dinner, 117.5 g carbohydrate, 57.4 g protein, 14.6 g fat, 831 kcal). In the afternoon and evening, patients had a cup of tea or coffee. Patients were free to drink water during the 24-hour study. Patients were not allowed to smoke. During the study, the patients were lodged in the research unit. During the day they were in upright position and were semiambulant. They spent their day sitting, watching television or reading, and taking short walks through the unit. From 11 PM until 7:30 AM the next day, the patients stayed in bed. The catheters were removed in the morning.
Manometric and pH recording technique
Twenty-four-hour ambulant manometric recordings of the pharynx, esophagus, LES, and stomach were obtained with a perfused 12-channel silicone rubber assembly with incorporated sleeve sensor (Dentsleeve, Adelaide, South Australia). The catheter (OD 3.5 mm, ID 0.4 mm) incorporated 4 pharyngeal sideholes (24, 26, 28, and 30 cm proximal to the proximal border of the sleeve), 3 esophageal sideholes (4, 9, and 14 cm proximal to the proximal border of the sleeve), a reversed perfused sleeve with 1 sidehole on its proximal border, and 1 intragastric sidehole (2 cm distal to the sleeve). Pressures were recorded with external pressure transducers (Abbott, Chicago, IL). The assembly was perfused at a rate of 0.08 mL/min with degassed water using hydraulic flow restrictors (Dentsleeve) and a low-compliance portable water pump consisting of a small gas cylinder and a water reservoir of 350 mL. The weights of the belt and the filled water pump are 0.5 kg and 3.3 kg, respectively. The water pump could be carried in a backpack to enable the patients to go from one room to another. The pump was refilled twice during the 24-hour study. The flow restrictors and pressure transducers were mounted on a belt.
The catheter was positioned with the proximal border of the sleeve 1 cm above the LES. After correct positioning of the assembly, the 2 pharyngeal pressure signals that provided optimal information about deglutition were selected. The other pharyngeal sideholes and the sidehole on the proximal border of the sleeve were capped off. A pH glass electrode with built-in reference (model LOT 440; Ingold A.G., Urdorf, Switzerland) was positioned at 5 cm proximal to the LES to record esophageal pH. Data were stored in a digital data logger (MMS; Enschede, The Netherlands). The sampling rate of the manometric signals was 4 Hz, except for the pharyngeal pressure signals, which were sampled at a rate of 8 Hz. The pH signal was sampled with a frequency of 1 Hz.
Before and after the study, the pH electrode was calibrated at 37°C using pH 4.0 and 7.0 buffer solutions (Radiometer analytical A/S, Bagsvaerd, Copenhagen) and the manometric assembly was calibrated at 0 and 50 cm H2O (0 and 5.0 kPa).
All analyses were performed with blinding relative to the presence or absence of hiatus hernia.
Esophageal acid exposure was analyzed using locally developed software. The incidence and duration of the reflux episodes were analyzed manually. A reflux episode was defined as either a decrease in pH to a value below 4 for at least 3 seconds or, when esophageal pH was already below 4, as a further abrupt decrease of at least 1 pH unit for at least 3 seconds. Reflux episodes during which esophageal clearance caused a transient shift to pH >4 followed by a return to pH <4 within 3 seconds were counted as 1 reflux episode.
Mean end-expiratory LES pressure was calculated automatically using the intragastric pressure as reference. During prolonged recording, some drift inevitably occurs in both the gastric and LES pressure channels. In addition, changes in body position lead to pressure offsets that are slightly different in the gastric and LES channels. Therefore, an algorithm was developed that continuously made minor adjustments to the gastric baseline curve. This adjustment was made when the lowest LES pressure in a 4-minute stretch differed from the gastric baseline pressure. If LES minimum pressure was lower than the lowest pressure in the gastric baseline curve during that period, the gastric baseline curve was corrected downward with a value of 0.2 kPa. If LES minimum pressure was higher than the gastric minimum for that period, an upward correction with 0.1 kPa was carried out. When pharyngeal contractions (swallows) were scarce (e.g., during the night), baseline update was postponed until at least 4 swallow-associated relaxations occurred. This is based on the observation that at least 25% of dry swallows are associated with complete LES relaxations.
The motor events underlying gastroesophageal reflux were detected manually and categorized as follows: transient LES relaxation (TLESR), swallow-associated prolonged LES relaxation (SAPLESR), swallow-associated normal LES relaxation (SANLESR), low LES pressure, straining, deep inspiration, and miscellaneous. A TLESR was defined as a decrease in LES pressure with a velocity ≥0.4 kPa/3 seconds, duration >10 seconds, nadir pressure ≤0.4 kPa, and absence of a swallow in the time window from 5 seconds before to 2 seconds after the start of the relaxation. Based on data from Mittal et al.,
TLESRs were also detected when, in the absence of a swallow in the above described time window, a sudden decrease (>50%) in the respiratory oscillations occurred that lasted at least 10 seconds and was associated with LESP ≤0.4 kPa. SAPLESR was defined similarly to TLESR but with the presence of a swallow in the swallow window. Low LES pressure was defined as a period of at least 30 seconds with end-expiratory LES pressure ≤0.4 kPa. Abdominal straining was detected as a sharp and brief increase in gastric pressure exceeding 2 times the normal respiratory pressure excursions, with a simultaneous elevation in esophageal pressures. Deep inspiration was defined as a sharp and brief increase in gastric pressure exceeding 2 times the normal respiratory pressure excursions, with a simultaneous decrease in esophageal pressures. A reflux episode was associated with straining or a deep inspiration if these events were detected within 5 seconds before the start of a reflux episode.
Reflux episodes were defined as miscellaneous when the reflux episode was associated with a multiple swallow-associated deep and prolonged LES relaxation or a TLESR shorter than 10 seconds and when no cause could be identified.
The percentage of TLESRs associated with acid reflux was calculated. For each reflux episode, the underlying motor mechanism was determined manually. Thereafter, the percentage of reflux episodes, the absolute number of reflux episodes, and the total reflux time associated with the underlying motor mechanisms were analyzed. All parameters were analyzed for the total 24-hour period. Esophageal acid exposure, basal LES pressure, and the distribution of the underlying mechanisms associated with acid reflux were also analyzed for the postprandial period (sum of the 2-hour periods after each meal), the interprandial daytime period (daytime period without the preprandial and postprandial periods), and the nighttime period (11 PM to 7:30 AM).
Comparisons between patients with and without hiatus hernia were performed using the nonparametric Mann–Whitney U test. A P value of <0.05 was considered significant. Data are presented as medians and interquartile ranges.
Mean recording time was 23.6 hours (22.6–24 hours). During all periods, except for the nighttime, esophageal acid exposure was significantly higher in patients with hiatus hernia than in patients without hiatus hernia (Table 1; Figure 1).
Table 1Reflux characteristics in GERD patients with and without a hiatus hernia
Patients with hiatus hernia also had a significantly higher incidence of reflux episodes (P < 0.001), but the mean duration of the reflux episode was not significantly different between the 2 groups.
The mechanisms underlying 1478 of the 1500 detected reflux episodes (98.5%) were analyzed. The remaining 1.5% could not be analyzed because of artifacts caused by movement or technical failures.
In both patients with and patients without hiatus hernia, almost all reflux episodes occurred when LES pressure was ≤0.4 kPa (97.6% [96.1%–99.3%] and 99.3% [97.6%–100%], respectively), whereas straining or deep inspiration without a simultaneous LES pressure of ≤0.4 kPa rarely was a cause of reflux, accounting for only 1.2% (0.7%–2.8%) and 0% (0%–2.7%), respectively. As shown in Figure 2, the distribution of the mechanisms underlying the individual reflux episodes was dependent on the presence or absence of hiatus hernia.Whereas most reflux episodes in patients without hiatus hernia were caused by TLESR and SAPLESR (60.2% [51.7%–68.2%] and 17.6% [9.3%–24.1%], respectively), in patients with hiatus hernia a more heterogeneous pattern of motor mechanisms was responsible for acid reflux. In the latter group, TLESR accounted for 32.8% (27.5%–41.0%), low LES pressure for 22.5% (15.5%–24.8%), straining at LES pressure of ≤0.4 kPa for 15.5% (11.1%–20.2%), and SANLESR for 13.8% (7.5%–15.0%) of the reflux episodes.
The proportions of reflux episodes associated with TLESRs and SAPLESRs were significantly higher in GERD patients without hiatus hernia than in those with. The proportions of reflux episodes associated with low LES pressure, SANLESR, and both straining and deep inspiration at LESP ≤0.4 kPa were significantly higher in patients with a hiatus hernia than in patients without. However, during all periods, comparable mean end-expiratory LES pressures were observed in patients with and without hiatus hernia (Figure 3 and Table 2).
Table 2LES pressure characteristics in GERD patients with and without a hiatus hernia
Furthermore, both groups showed comparable incidences of TLESRs and proportions of TLESRs associated with acid reflux.
The increased number of reflux episodes in patients with hiatus hernia appeared to be explained by an increased number of reflux episodes caused by SANLESRs, low LES pressure, and both straining and deep inspiration at LES pressure ≤0.4 kPa (Figure 4).The incidences of reflux episodes associated with both TLESRs and SAPLESRs were similar in patients with and without hiatus hernia. Likewise, a significantly higher total reflux time in patients with hiatus hernia was associated with SANLESRs (318 seconds [160–611 seconds] vs. 55 seconds [19–94 seconds]); P < 0.04), low LES pressure (1879 seconds [850–5397 seconds] vs. 37 seconds [0–83 seconds]; P < 0.001), straining at LES pressure ≤ 0.4 kPa (831 seconds [548–1479 seconds] vs. 50.0 seconds [2–155 seconds]; P < 0.001), deep inspiration at LES pressure ≤ 0.4 kPa (16 seconds [5–56 seconds] vs. 0 seconds [0–0 seconds]; P = 0.01), and straining at LES pressure > 0.4 kPa (12 seconds [0–129 seconds] vs. 0 seconds [0–0 seconds]; P < 0.05).
Additional detailed analysis of the reflux events related to both straining and deep inspiration occurring during TLESRs, SAPLESRs, and SANLESRs showed no significant differences between the 2 groups (data not shown). However, the numbers of reflux episodes associated with straining and deep inspiration during low LES pressure were significantly higher in patients with hiatus hernia than in those without (6.0 [3.3–10.3] vs. 0 [0–0], P < 0.001, and 0.5 [0–1] vs. 0 [0–0], P = 0.02, respectively).
As shown in Figure 5, during all periods TLESRs and SAPLESRs were the predominant mechanisms of reflux in patients without hiatus hernia.In patients with hiatus hernia, the distribution of the underlying motor events was markedly different in the different time periods. A low LES pressure and SANLESRs were more often the mechanism of reflux in the postprandial period than in the interprandial period. During the night, TLESRs and low LES pressure were less frequently the underlying motor events of reflux than during the interprandial and postprandial periods, whereas straining with and without coexisting LES pressure ≤0.4 kPa, SAPLESRs, and SANLESRs were more often observed.
Patients with esophagitis (n = 14) had higher acid exposure than patients without esophagitis (7.6 [6.1–11.3] vs. 3.0 [2.5–3.6]; P = 0.001). This was caused by a higher incidence of reflux episodes (3.0 [2.0–4.0] vs. 2.1 [1.8–3.1]; P = 0.04). The esophagitis patients had more reflux episodes associated with a low LES pressure (12.6 [7.6–22.8] vs. 2.0 [0.75–4]; P = 0.03). The relative contributions of other reflux mechanisms were similar in patients with and without esophagitis.
This study addressed the relationship between hiatus hernia and the motor events underlying gastroesophageal reflux during a 24-hour period in ambulant GERD patients.
As anticipated, patients with hiatus hernia had greater esophageal acid exposure. This was caused by a higher incidence of acid reflux episodes, whereas the duration of the reflux episodes was not affected by the presence of a hiatus hernia. The higher incidence of reflux episodes could not be explained by an increased incidence of TLESRs or an increased proportion of TLESRs associated with acid reflux. TLESR and SAPLESR were the most important motor events underlying acid reflux in patients without hiatus hernia, accounting for approximately 80% of all reflux episodes. In contrast, a more heterogeneous pattern of motor mechanisms was observed in patients with hiatus hernia, and only approximately 40% of the reflux episodes were related to TLESRs and SAPLESRs.
Our study showed that in GERD patients with hiatus hernia, a substantial proportion of reflux episodes is associated with low LES pressure, whereas in patients without hiatus hernia reflux associated with low LES pressure is rare. Because comparable mean LES pressures were found in patients with and without hiatus hernia, our observations indicate that the increased prevalence of reflux during periods with low LES pressure in patients with hiatus hernia is caused by other factors. The most likely candidate for this is the abnormal position of the crural diaphragm. The hypothesis that the crural diaphragm is of crucial importance in the prevention of gastroesophageal reflux during periods with low LES pressure is supported by other studies.
One of these showed that during prolonged complete LES relaxations induced by pharyngeal stimulation with water, no reflux occurred, whereas the only difference between these LES relaxations and TLESRs was the absence of a simultaneous inhibition of the crural diaphragm.
Another difference between patients with and without hiatus hernia observed in this study was the increased number of reflux episodes associated with a swallow-associated normal LES relaxation (SANLESR) in patients with hiatus hernia. Radiologic studies in patients with nonreducible hiatus hernia have shown that barium is trapped in the hiatal sac and that it subsequently refluxes into the esophagus during a second swallow.
Therefore, it is likely that the higher incidence of reflux episodes associated with SANLESR in GERD patients with hiatus hernia is caused by reflux of acid from the hiatal sac.
In agreement with other studies, we rarely observed reflux related to deep inspiration or abdominal straining without a coexistent low LES pressure, both in patients with and in patients without hiatus hernia.
However, when straining or deep inspiration occurred during a period with LESP ≤0.4 kPa, a reflux episode occurred more frequently in both groups, but much more so in patients with a hiatus hernia. Both events are normally associated with contractions of the crural diaphragm resulting in increased pressure at the esophageal barrier.
The higher incidence of reflux episodes associated with straining and deep inspiration during periods of low LES pressure that was observed in patients with hiatus hernia is consistent with the hypothesis that in these patients the function of the gastroesophageal barrier is impaired by improper position of the LES with respect to the crural diaphragm. These observations are in accordance with findings reported by Sloan et al. who recorded a higher number of reflux episodes associated with leg raising, Valsalva maneuver, the Müller maneuver (strong respiratory effort with closed glottis), and coughing in hiatus hernia patients than in healthy subjects without hiatus hernia.
showed that in patients with hiatus hernia, 2 separate high-pressure zones exist, representing the LES and the crural diaphragm, and that summation of the pressures of these 2 segments results in a profile similar to that found in healthy subjects. The outcome of our study supports their hypothesis that the intrinsic and extrinsic pressures are additive when superimposed.
The proportion of our patients with esophagitis was higher in the subgroup with hiatus hernia (10/12) than in the subgroup without (4/10), and the patients with esophagitis had a higher number of reflux episodes associated with a low LESP than those without. Therefore, one could argue that the observed differences in reflux mechanisms between patients with and without hiatus are partly a result of the presence of esophagitis. We do not consider this a likely scenario for several reasons. First, our patients had low-grade esophagitis (grades 1–2). Second, there is no indication that the presence of esophagitis would lead to an alteration of LES function, whereas there is good evidence that the presence of a hiatus hernia affects reflux mechanisms.
The effect of hiatus hernia on the underlying mechanisms of reflux shown in our study might explain the observed scatter of the results obtained in several of the previous studies on reflux mechanisms.
The relatively low proportion of reflux episodes associated with TLESRs and SAPLESRs in patients with hiatus hernia in our study is an important observation in respect to medical treatment of patients with GERD. Reduction of gastric acid secretion is the most successful current medical treatment for GERD. However, in recent years efforts are being made to develop drugs with an inhibitory effect on the incidence of TLESRs. However, our data suggest that the efficacy of these drugs for treatment of GERD might be disappointing in patients with hiatus hernia because only partial reduction of their gastroesophageal reflux will be achieved.
In conclusion, this study shows that in ambulatory GERD patients, the mechanisms leading to reflux are different in patients with hiatus hernia than in those without. Whereas the incidence of reflux episodes caused by TLESRs in patients with hiatus hernia is similar to that in patients without hiatus hernia, other mechanisms such as low LES pressure, swallow-associated LES relaxations, and straining are responsible for the increased esophageal acid exposure associated with the presence of hiatus hernia. These findings underline the importance of the crural diaphragm, which, when surrounding the LES, protects against reflux during periods of low LES pressure.
Mechanisms of gastroesophageal reflux in patients with reflux esophagitis.
☆Address requests for reprints to: Margot A. van Herwaarden, M.D, Ph.D., University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. e-mail: [email protected] ; fax: (31) 30-2505533.
☆☆M. Samsom is a fellow of the Royal Netherlands Academy of Arts and Science.