Original Paper Received: June 5, 2014 Accepted: August 15, 2014 Published online: March 7, 2015
Digestion 2015;91:181–186 DOI: 10.1159/000367650
Effects of Aging and Acid Reflux on Esophageal Motility Noriyuki Kawami a Katsuhiko Iwakiri a, b Hirohito Sano a Yuriko Tanaka a Choitsu Sakamoto a a b
Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Tokyo and Department of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai City, Japan
Key Words Aging · Acid reflux · Reflux esophagitis · Esophageal motility · Esophageal manometry
cantly lower than in young HS. Conclusions: Aging may cause a decrease in the success rate of SP, and acid reflux itself may cause a decrease of the DCI in PP and SP. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 0012–2823/15/0913–0181$39.50/0 E-Mail [email protected] www.karger.com/dig
Introduction
While it has been reported that aging can have a minor effect on esophageal motility [1], it has also been reported, from manometry examinations, that many elderly people with esophageal dysmotility have decreased amplitude of esophageal contractions, a lower success rate of primary peristalsis, and decreased lower esophageal sphincter (LES) pressure [2–4] and that the prevalence of reflux esophagitis (RE) does increase with age [5]. In general, when considering these results, a decrease in esophageal motility from aging may indeed be a cause of RE. It is also possible that reflux itself causes a decrease in esophageal motility as esophageal acid exposure in patients with RE increases according to the severity of RE [6]. Kahrilas et al. have reported that peristaltic dysfuncKatsuhiko Iwakiri, MD, PhD Department of Gastroenterology Nippon Medical School Chiba Hokusoh Hospital 1715, Inzai City, Chiba 270–1694 (Japan) E-Mail k-iwa @ nms.ac.jp
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Abstract Backgrounds: It is generally thought that esophageal motility decreases with age; however, a decrease in esophageal motility may also be caused by esophagitis. The aim of this study is to investigate the effects of aging and acid reflux on esophageal motility. Methods: 40 young (under 45) healthy subjects (HS), 40 elderly (over 65) HS, and 40 elderly (over 65) patients with mild reflux esophagitis (RE), underwent esophageal high-resolution manometry (HRM). Lower esophageal sphincter pressure (LESP), primary peristalsis (PP), and secondary peristalsis (SP) were evaluated. Results: There was no difference in the LESP and also in the success rate of PP between young and elderly HS or between elderly HS and RE. There was no difference in the distal contractile integral (DCI) of PP and SP between the young and elderly HS, but in the elderly RE, it was significantly lower than in the elderly HS. There was no difference in the success rate of SP between elderly HS and RE, but in elderly HS it was signifi-
Table 1. Characteristics of young healthy subjects (HS) aged under 45, elderly HS aged over 65, and elderly patients with mild reflux esophagitis (RE) of Los Angeles classification grades A or B aged over 65
Characteristic
Young HS (65)
Elderly RE (>65)
Patients, n Age, years Gender (male/female) Body mass index, kg/m2 Hiatus hernia (>2 cm)
40 37.0 (33.5–40.0) 23/17 20.6 (18.4–22.8) 0
40 74.0 (70.0–78.0) 18/22 22.1 (19.4–24.5) 2
40 70.0 (66.0–75.0) 17/23 23.7 (22.3–24.9) 5
Median (interquartile range).
Methods
above the distal end of the assembly, monitored pressure from the proximal stomach, LES, and distal esophagus. A further seven side holes, spaced at 2-cm intervals, monitored pressure from the distal to the proximal esophagus and four side holes, at 3, 6, 10, 13 cm above the most proximal of the 2-cm interval side holes, monitored pressure from the proximal esophagus to the pharynx. Each lumen was perfused with degassed distilled water at 0.15 ml/min by a low-compliance manometric infusion pump (Dentsleeve Pty Ltd., Wayville, Australia). Data were digitized via a computer and the digitized signals were displayed, stored, and analyzed using Trace! Software (Dr. G.S. Hebbard, The Royal Melbourne Hospital, Parkville, Vic., Australia). Study Protocol Subjects were studied after they fasted overnight; the manometric assembly was positioned and after 10 min of accommodation, each subject was assessed for basal LES pressure and primary and secondary peristalsis. Basal LES pressure was measured for 10 minutes and then primary peristalsis was tested with 5 ml water swallows, each swallow being separated by a 30-s interval and the process repeated 10 times. Secondary peristalsis was then triggered by esophageal distention using a 20 ml bolus of air, which was injected rapidly into the middle esophagus by hand. After 20 s, each stimulus was followed by a dry swallow to clear any residual air and repeated 5 times.
Subjects Subjects were composed of 40 young (under 45 years) healthy subjects (HS) aged 20–45 (23 men, median age 37.0 years), 40 elderly (over 65 years) HS aged 65–85 (18 men, median age 74.0 years), and 40 elderly (over 65 years) patients with mild RE (elderly RE) of Los Angeles classification grades A or B aged 65–79 (17 men, median age 70.0 years). All healthy subjects were free of gastrointestinal symptoms with no esophageal mucosal break in their endoscopic findings. In addition, none was taking medication known to influence esophageal motor function or had any history of connective tissue disease, diabetes, or neurologic disorders. Table 1 shows the characteristics of the subjects. There was no difference in the body mass index (BMI) between the young HS and the elderly HS and between the elderly HS and the elderly RE. In the endoscopic findings, 2 elderly HS and 5 elderly RE had a hiatus hernia greater than 2 cm but the young HS had no hiatus hernia (table 1). Informed consent was obtained from each subject and the Ethics Committee for Human Research approved the study at Nippon Medical School.
Data Analysis End expiratory basal LES pressure was referenced to end expiratory intragastric pressure and determined at one-minute intervals by taking a visual mean, and mean values were calculated for a period of 10 min. Primary and secondary peristalsis was classified as successful if a pressure wave of greater than 12 mm Hg in the three proximal esophageal body channels and greater than 25 mm Hg in the distal esophageal channels traversed all the recording sites [9, 10]. Peristaltic progression was defined as peristaltic velocity of less than 6 cm/s [10, 11] and the vigor of the esophageal contraction in both primary and secondary peristalsis was estimated by the distal contractile integral (DCI). DCI is defined as volume of domain above 20 mm Hg of the distal esophageal segment [12].
Recording Methods Esophageal manometry was carried out with a 21-channel manometric assembly (Dentsleeve Pty Ltd., Wayville, Australia). Ten side holes, which were spaced at 1-cm intervals starting at 3 cm
Statistical Analysis All data were presented as median, interquartile range, and values for basal LES pressure, the success rates of primary and secondary peristalsis, and the DCI of primary and secondary peristalsis
182
Digestion 2015;91:181–186 DOI: 10.1159/000367650
Kawami/Iwakiri/Sano/Tanaka/Sakamoto
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tion is increasingly prevalent with the increasing severity of RE [7] and Sugiura et al. have reported that distal esophageal motility, in patients with RE, decreases according to the severity of RE. There is no difference however in esophageal motility in the proximal esophagus between patients with RE and healthy subjects, where it is less likely that refluxed acid comes up [8]. These results suggest that peristaltic dysfunction in patients with RE may be the result of the reflux itself; therefore, the effects of aging and acid reflux itself, on esophageal motility, remains unclear. The aim of this study was to investigate the effects of aging and acid reflux on esophageal motility using high-resolution manometry (HRM).
n.s. 22
n.s.
n.s.
100
20
90
16
80
14
70
12
60
10
50
%
mm Hg
18
8
40
6
30
4
20
2 0
n.s.
Young HS
Elderly HS
10
Elderly RE
0
Young HS
Elderly RE
Elderly HS
Fig. 1. The basal lower esophageal sphincter (LES) pressure in the
Fig. 2. The success rate of primary peristalsis in the young healthy
young healthy subjects (HS), the elderly HS, and the elderly patients with reflux esophagitis (RE). Data are presented as median (interquartile range). n.s. = Not significant.
subjects (HS), the elderly HS, and the elderly patients with reflux esophagitis (RE). Data are presented as median (interquartile range). n.s. = Not significant.
were determined for each subject. From these, median values were calculated for the group as a whole and all data were analyzed with the Mann-Whitney U-test. Statistical significance was accepted when p < 0.05.
n.s.
2,000
p = 0.0029
1,800 1,600
Primary Peristalsis There was no difference in the success rate of primary peristalsis between the young HS (90% [50–100]) and the elderly HS (90 [65–100]) and between the elderly HS and the elderly RE (80 [60–100]) (fig. 2). There was no difference in the DCI between the young HS (805 mm Hg-s-cm [388–1,176]) and the elderly HS (782 [387–1,227]) (fig. 3) but the DCI in the elderly RE (357 [261–662]) was significantly lower (p = 0.0029) than that in the elderly HS (fig. 3). Secondary Peristalsis The success rate of secondary peristalsis in the elderly HS (40% [20–80]) was significantly lower (p < 0.001) than that in the young HS (80 [60–100]) (fig. 4) but there was no Aging and Esophageal Motility
1,200 1,000 800 600 400 200 0
Young HS
Elderly HS
Elderly RE
Fig. 3. The distal contractile integral (DCI) of primary peristalsis
in the young healthy subjects (HS), the elderly HS, and the elderly patients with reflux esophagitis (RE). Data are presented as median (interquartile range). n.s. = Not significant.
difference in the success rate of secondary peristalsis between the elderly HS and the elderly RE (40 [20–60]) (fig. 4). There was no difference in the DCI of secondary peristalsis between the young HS (714 mm Hg-s-cm [438– 1,121]) and the elderly HS (720 [393–1,601]) (fig. 5) but in the elderly RE (557 [329–684]) it was significantly lower (p = 0.0277) than in the elderly HS (fig. 5). Digestion 2015;91:181–186 DOI: 10.1159/000367650
183
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Basal LES Pressure There was no difference in the basal LES pressure between the young HS (10.6 mm Hg [8.0–13.4]) and the elderly HS (12.0 [9.4–14.7]) and between the elderly HS and the elderly RE (10.3 [8.1–17.2]) (fig. 1).
mm Hg-s-cm
1,400
Results
p < 0.001
n.s.
2,000
80
1,800 mm Hg-s-cm
70 60 50 40 30
1,600 1,400 1,200 1,000 800 600
20
400
10
200 0 Young HS
Elderly HS
Elderly RE
Young HS
Elderly HS
Elderly RE
Fig. 4. The success rate of secondary peristalsis in the young healthy
Fig. 5. The distal contractile integral (DCI) of secondary peristalsis
subjects (HS), the elderly HS, and the elderly patients with reflux esophagitis (RE). Data are presented as median (interquartile range). n.s. = Not significant.
in the young healthy subjects (HS), the elderly HS, and the elderly patients with reflux esophagitis (RE). Data are presented as median (interquartile range). n.s. = Not significant.
Discussion
New diagnostic criteria and classification (Chicago classification) of esophageal motility disorder for HRM with 36 channels, spaced at 1-cm intervals, were introduced [12]. In these criteria, the vigor of the esophageal contraction was estimated by the DCI (amplitude × duration × length [mm Hg-s-cm] of the distal esophageal contraction >20 mm Hg from proximal to distal pressure troughs). Peristaltic propagation was evaluated from the length of the peristaltic break, distal latency (DL), and contractile front velocity (CFV). In this study, esophageal manometry was carried out with a 21-channel manometric assembly, in which the side holes were spaced at 1-cm intervals from the proximal stomach to the distal esophagus, at 1 to 2-cm intervals at the middle esophagus and 2 to 3-cm intervals at the proximal esophagus. Although the manometry system we use with 21 channels is different from the HRM system with 36 channels, it is considered that the calculated value of the DCI is very similar to that of the HRM system with 36 channels. However, with regard to the success rate of peristalsis, we were unable to use the criteria of the Chicago classification because it was not possible to evaluate peristaltic breaks correctly in our manometry system. We therefore evaluated the success rate of peristalsis using previous criteria [9–11]. With regard to the effect of aging on esophageal motility, any differences between young HS and elderly HS 184
Digestion 2015;91:181–186 DOI: 10.1159/000367650
were compared but the lower success rate of secondary peristalsis in elderly HS was the only difference between these groups. First, this result suggested that if subjects have no reflux symptoms, such as heartburn, aging has no effect on basal LES pressure, the DCI, or the success rate of primary peristalsis. Second, that aging does contribute to a decrease in the success rate of secondary peristalsis. There has been only one study carried out on the effect of aging on secondary peristalsis where Ren et al. reported that the success rate of secondary peristalsis in elderly HS is significantly lower than in young HS [13]. Although their result is consistent with our result, their research was carried out on fewer subjects compared with ours. This study therefore is the first study, using a significant number of subjects simultaneously, in which the effects of aging on primary peristalsis, secondary peristalsis, and basal LES pressure were examined. There is less possibility that a motor nerve or the esophageal muscle itself would cause a decrease in the success rate of secondary peristalsis in elderly HS because there is no difference in the DCI between the young and elderly HS. We did consider however, that abnormal processing in the brain or a decrease in the perception of esophageal mucosa as a cause of the decrease in the success rate of secondary peristalsis in elderly HS. Meciano et al. reported that at necropsy, the number of neurons in the myenteric plexus of the esophagus in the elderly was less significant than in the young [14]. Kawami/Iwakiri/Sano/Tanaka/Sakamoto
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%
p = 0.0277
2,200
90
0
n.s.
2,400
100
This decrease in neurons in the elderly may be one of the causes of the decreased success rate of secondary peristalsis; however, it is not clear why only sensory neurons are impaired and motor neurons remain intact. Further study is required. In cases where acid reflux occurs while asleep, secondary peristalsis is very important in clearing refluxed acid from the esophagus into the stomach; however, the act of swallowing does not occur during sleep because saliva secretion is inhibited. If secondary peristalsis does not occur after nocturnal acid reflux, refluxed acid stays in the esophagus for a longer period of time and could possibly lead to excessive esophageal acid exposure, a cause of RE; therefore, even elderly people with no RE should avoid eating three hours before going to sleep. When considering the effect of acid reflux on esophageal motility, differences between elderly HS and elderly RE were compared. In this study, young patients with mild RE were not included as subjects, because generally speaking, the duration of the disease in young patients with RE is shorter than in elderly patients with RE and it is considered therefore, that the effect of acid reflux on esophageal motility in young patients with RE is less than in elderly patients with RE. In consideration of this possibility, the differences between elderly HS and elderly patients with RE were compared. The DCI of primary and secondary peristalsis in the elderly RE was significantly lower than in the elderly HS, which means that acid reflux itself may cause esophageal dysmotility. In the previous study, LES pressure, the success rate, and the amplitude of primary peristalsis in patients with RE increased after treatment, compared with
before treatment [15]. In some animal experiments, it has been reported that LES pressure or the amplitude of peristalsis decreased after experimental esophagitis [16– 18]. These results are consistent with our results; however, there is a contrary view. It is known that collagen disease is associated with a high prevalence of esophageal dysmotility [19] and it has been reported that many patients with collagen disease also have severe RE [20], which means that esophageal dysmotility causes RE. With regard to the cause of the decrease in the DCI in peristalsis in patients with RE, it is considered that proinflammatory cytokines IL-1β and IL-6 are produced as a result of esophagitis and these cytokines contribute to a decrease in an esophageal contraction by inhibiting the release of ACh from the myenteric neurons [21]. This may be the reason that esophageal motility decreases even if inflammation doesn’t reach the muscular layer. In conclusion, aging may be one of the causes for the decrease in the success rate of secondary peristalsis and as well acid reflux itself may cause a decrease in the DCI in primary and secondary peristalsis.
Disclosure Statement Dr. Iwakiri has received lecture fee from Takeda Pharmaceuticals Co. Ltd., and Eisai Co. Ltd. Dr. Sakamoto has served as a consultant and speaker for Astellas Pharma Inc., AstraZeneca, Eisai Co. Ltd., Otsuka Pharmaceuticals Co. Ltd., Pfizer Japan Inc., and Takeda Pharmaceuticals Co. Ltd. Dr. Sakamoto has also received grant/research support from Astellas Pharma Inc., AstraZeneca, Eisai Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Co. Ltd.
References
Aging and Esophageal Motility
5 Menon S, Jayasena H, Nightingale P, Trudgill NJ: Influence of age and sex on endoscopic findings of gastrooesophageal reflux disease: an endoscopy database study. Eur J Gastroenterol Hepatol 2011;23:389–395. 6 Kasapidis P, Xynos E, Mantides A, Chrysos E, Demonakou M, Nikolopoulos N, Vassilakis JS: Differences in manometry and 24-h ambulatory pH-metry between patients with and without endoscopic or histological esophagitis in gastroesophageal reflux disease. Am J Gastroenterol 1993;88:1893–1899. 7 Kahrilas PJ, Dodds WJ, Hogan WJ, Kern M, Arndorfer RC, Reece A: Esophageal peristaltic dysfunction in peptic esophagitis. Gastroenterology 1986;91:897–904. 8 Sugiura T, Iwakiri K, Kotoyori M, Kobayashi M: Relationship between severity of reflux
esophagitis according to the Los Angeles classification and esophageal motility. J Gastroenterol 2001;36:226–230. 9 Schoeman MN, Holloway RH: Stimulation and characteristics of secondary oesophageal peristalsis in normal subjects. Gut 1994; 35: 152–158. 10 Iwakiri K, Hayashi Y, Kotoyori M, Tanaka Y, Kawami N, Sano H, Takubo K, Sakamoto C, Holloway RH: Defective triggering of secondary peristalsis in patients with non-erosive reflux disease. J Gastroenterol Hepatol 2007;22: 2208–2211. 11 Hewson EG, Ott DJ, Dalton CB, Chen YM, Wu WC, Richter JE: Manometry and radiology. Complementary studies in the assessment of esophageal motility disorders. Gastroenterology 1990;98:626–632.
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1 Adamek RJ, Wegener M, Wienbeck M, Gielen B: Long-term esophageal manometry in healthy subjects. Evaluation of normal values and influence of age. Dig Dis Sci 1994; 39: 2069–2073. 2 Achem AC, Achem SR, Stark ME, DeVault KR: Failure of esophageal peristalsis in older patients: association with esophageal acid exposure. Am J Gastroenterol 2003; 98: 35– 39. 3 Nishimura N, Hongo M, Yamada M, Kawakami H, Ueno M, Okuno Y, Toyota T: Effect of aging on the esophageal motor functions. J Smooth Muscle Res 1996;32:43–50. 4 Ferriolli E, Oliveira RB, Matsuda NM, Braga FJ, Dantas RO: Aging, esophageal motility, and gastroesophageal reflux. J Am Geriatr Soc 1998;46:1534–1537.
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15 Marshall JB, Gerhardt DC: Improvement in esophageal motor dysfunction with treatment of reflux esophagitis: a report of two cases. Am J Gastroenterol 1982;77:351–354. 16 Eastwood GL, Castell DO, Higgs RH: Experimental esophagitis in cats impairs lower esophageal sphincter pressure. Gastroenterology 1975;69:146–153. 17 Shirazi S, Schulze-Delrieu K, Custer-Hagen T, Brown CK, Ren J: Motility changes in opossum esophagus from experimental esophagitis. Dig Dis Sci 1989;34:1668–1676. 18 Zhang X, Geboes K, Depoortere I, Tack J, Janssens J, Sifrim D: Effect of repeated cycles of acute esophagitis and healing on esophageal peristalsis, tone, and length. Am J Physiol Gastrointest Liver Physiol 2005;288:G1339–G1346.
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19 Wegener M, Adamek RJ, Wedmann B, Jergas M, Altmeyer P: Gastrointestinal transit through esophagus, stomach, small and large intestine in patients with progressive systemic sclerosis. Dig Dis Sci 1994;39:2209–2215. 20 Zamost BJ, Hirschberg J, Ippoliti AF, Furst DE, Clements PJ, Weinstein WM: Esophagitis in scleroderma. Prevalence and risk factors. Gastroenterology 1987;92:421–428. 21 Cao W, Cheng L, Behar J, Fiocchi C, Biancani P, Harnett KM: Proinflammatory cytokines alter/reduce esophageal circular muscle contraction in experimental cat esophagitis. Am J Physiol Gastrointest Liver Physiol 2004; 287:G1131–G1139.
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12 Bredenoord AJ, Fox M, Kahrilas PJ, Pandolfino JE, Schwizer W, Smout AJ: Chicago classification criteria of esophageal motility disorders defined in high resolution esophageal pressure topography. Neurogastroenterol Motil 2012;24(suppl 1):57–65. 13 Ren J, Shaker R, Kusano M, Podvrsan B, Metwally N, Dua KS, Sui Z: Effect of aging on the secondary esophageal peristalsis: presbyesophagus revisited. Am J Physiol 1995; 268:G772–G779. 14 Meciano Filho J, Carvalho VC, de Souza RR: Nerve cell loss in the myenteric plexus of the human esophagus in relation to age: a preliminary investigation. Gerontology 1995; 41: 18–21.
Digestion 2015;91:181–186 DOI: 10.1159/000367650
Effects of Aging and Acid Reflux on Esophageal Motility Noriyuki Kawami a Katsuhiko Iwakiri a, b Hirohito Sano a Yuriko Tanaka a Choitsu Sakamoto a a b
Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Tokyo and Department of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai City, Japan
Key Words Aging · Acid reflux · Reflux esophagitis · Esophageal motility · Esophageal manometry
cantly lower than in young HS. Conclusions: Aging may cause a decrease in the success rate of SP, and acid reflux itself may cause a decrease of the DCI in PP and SP. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 0012–2823/15/0913–0181$39.50/0 E-Mail [email protected] www.karger.com/dig
Introduction
While it has been reported that aging can have a minor effect on esophageal motility [1], it has also been reported, from manometry examinations, that many elderly people with esophageal dysmotility have decreased amplitude of esophageal contractions, a lower success rate of primary peristalsis, and decreased lower esophageal sphincter (LES) pressure [2–4] and that the prevalence of reflux esophagitis (RE) does increase with age [5]. In general, when considering these results, a decrease in esophageal motility from aging may indeed be a cause of RE. It is also possible that reflux itself causes a decrease in esophageal motility as esophageal acid exposure in patients with RE increases according to the severity of RE [6]. Kahrilas et al. have reported that peristaltic dysfuncKatsuhiko Iwakiri, MD, PhD Department of Gastroenterology Nippon Medical School Chiba Hokusoh Hospital 1715, Inzai City, Chiba 270–1694 (Japan) E-Mail k-iwa @ nms.ac.jp
Downloaded by: Freie Universität Berlin 130.133.8.114 - 5/10/2015 3:01:22 AM
Abstract Backgrounds: It is generally thought that esophageal motility decreases with age; however, a decrease in esophageal motility may also be caused by esophagitis. The aim of this study is to investigate the effects of aging and acid reflux on esophageal motility. Methods: 40 young (under 45) healthy subjects (HS), 40 elderly (over 65) HS, and 40 elderly (over 65) patients with mild reflux esophagitis (RE), underwent esophageal high-resolution manometry (HRM). Lower esophageal sphincter pressure (LESP), primary peristalsis (PP), and secondary peristalsis (SP) were evaluated. Results: There was no difference in the LESP and also in the success rate of PP between young and elderly HS or between elderly HS and RE. There was no difference in the distal contractile integral (DCI) of PP and SP between the young and elderly HS, but in the elderly RE, it was significantly lower than in the elderly HS. There was no difference in the success rate of SP between elderly HS and RE, but in elderly HS it was signifi-
Table 1. Characteristics of young healthy subjects (HS) aged under 45, elderly HS aged over 65, and elderly patients with mild reflux esophagitis (RE) of Los Angeles classification grades A or B aged over 65
Characteristic
Young HS (65)
Elderly RE (>65)
Patients, n Age, years Gender (male/female) Body mass index, kg/m2 Hiatus hernia (>2 cm)
40 37.0 (33.5–40.0) 23/17 20.6 (18.4–22.8) 0
40 74.0 (70.0–78.0) 18/22 22.1 (19.4–24.5) 2
40 70.0 (66.0–75.0) 17/23 23.7 (22.3–24.9) 5
Median (interquartile range).
Methods
above the distal end of the assembly, monitored pressure from the proximal stomach, LES, and distal esophagus. A further seven side holes, spaced at 2-cm intervals, monitored pressure from the distal to the proximal esophagus and four side holes, at 3, 6, 10, 13 cm above the most proximal of the 2-cm interval side holes, monitored pressure from the proximal esophagus to the pharynx. Each lumen was perfused with degassed distilled water at 0.15 ml/min by a low-compliance manometric infusion pump (Dentsleeve Pty Ltd., Wayville, Australia). Data were digitized via a computer and the digitized signals were displayed, stored, and analyzed using Trace! Software (Dr. G.S. Hebbard, The Royal Melbourne Hospital, Parkville, Vic., Australia). Study Protocol Subjects were studied after they fasted overnight; the manometric assembly was positioned and after 10 min of accommodation, each subject was assessed for basal LES pressure and primary and secondary peristalsis. Basal LES pressure was measured for 10 minutes and then primary peristalsis was tested with 5 ml water swallows, each swallow being separated by a 30-s interval and the process repeated 10 times. Secondary peristalsis was then triggered by esophageal distention using a 20 ml bolus of air, which was injected rapidly into the middle esophagus by hand. After 20 s, each stimulus was followed by a dry swallow to clear any residual air and repeated 5 times.
Subjects Subjects were composed of 40 young (under 45 years) healthy subjects (HS) aged 20–45 (23 men, median age 37.0 years), 40 elderly (over 65 years) HS aged 65–85 (18 men, median age 74.0 years), and 40 elderly (over 65 years) patients with mild RE (elderly RE) of Los Angeles classification grades A or B aged 65–79 (17 men, median age 70.0 years). All healthy subjects were free of gastrointestinal symptoms with no esophageal mucosal break in their endoscopic findings. In addition, none was taking medication known to influence esophageal motor function or had any history of connective tissue disease, diabetes, or neurologic disorders. Table 1 shows the characteristics of the subjects. There was no difference in the body mass index (BMI) between the young HS and the elderly HS and between the elderly HS and the elderly RE. In the endoscopic findings, 2 elderly HS and 5 elderly RE had a hiatus hernia greater than 2 cm but the young HS had no hiatus hernia (table 1). Informed consent was obtained from each subject and the Ethics Committee for Human Research approved the study at Nippon Medical School.
Data Analysis End expiratory basal LES pressure was referenced to end expiratory intragastric pressure and determined at one-minute intervals by taking a visual mean, and mean values were calculated for a period of 10 min. Primary and secondary peristalsis was classified as successful if a pressure wave of greater than 12 mm Hg in the three proximal esophageal body channels and greater than 25 mm Hg in the distal esophageal channels traversed all the recording sites [9, 10]. Peristaltic progression was defined as peristaltic velocity of less than 6 cm/s [10, 11] and the vigor of the esophageal contraction in both primary and secondary peristalsis was estimated by the distal contractile integral (DCI). DCI is defined as volume of domain above 20 mm Hg of the distal esophageal segment [12].
Recording Methods Esophageal manometry was carried out with a 21-channel manometric assembly (Dentsleeve Pty Ltd., Wayville, Australia). Ten side holes, which were spaced at 1-cm intervals starting at 3 cm
Statistical Analysis All data were presented as median, interquartile range, and values for basal LES pressure, the success rates of primary and secondary peristalsis, and the DCI of primary and secondary peristalsis
182
Digestion 2015;91:181–186 DOI: 10.1159/000367650
Kawami/Iwakiri/Sano/Tanaka/Sakamoto
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tion is increasingly prevalent with the increasing severity of RE [7] and Sugiura et al. have reported that distal esophageal motility, in patients with RE, decreases according to the severity of RE. There is no difference however in esophageal motility in the proximal esophagus between patients with RE and healthy subjects, where it is less likely that refluxed acid comes up [8]. These results suggest that peristaltic dysfunction in patients with RE may be the result of the reflux itself; therefore, the effects of aging and acid reflux itself, on esophageal motility, remains unclear. The aim of this study was to investigate the effects of aging and acid reflux on esophageal motility using high-resolution manometry (HRM).
n.s. 22
n.s.
n.s.
100
20
90
16
80
14
70
12
60
10
50
%
mm Hg
18
8
40
6
30
4
20
2 0
n.s.
Young HS
Elderly HS
10
Elderly RE
0
Young HS
Elderly RE
Elderly HS
Fig. 1. The basal lower esophageal sphincter (LES) pressure in the
Fig. 2. The success rate of primary peristalsis in the young healthy
young healthy subjects (HS), the elderly HS, and the elderly patients with reflux esophagitis (RE). Data are presented as median (interquartile range). n.s. = Not significant.
subjects (HS), the elderly HS, and the elderly patients with reflux esophagitis (RE). Data are presented as median (interquartile range). n.s. = Not significant.
were determined for each subject. From these, median values were calculated for the group as a whole and all data were analyzed with the Mann-Whitney U-test. Statistical significance was accepted when p < 0.05.
n.s.
2,000
p = 0.0029
1,800 1,600
Primary Peristalsis There was no difference in the success rate of primary peristalsis between the young HS (90% [50–100]) and the elderly HS (90 [65–100]) and between the elderly HS and the elderly RE (80 [60–100]) (fig. 2). There was no difference in the DCI between the young HS (805 mm Hg-s-cm [388–1,176]) and the elderly HS (782 [387–1,227]) (fig. 3) but the DCI in the elderly RE (357 [261–662]) was significantly lower (p = 0.0029) than that in the elderly HS (fig. 3). Secondary Peristalsis The success rate of secondary peristalsis in the elderly HS (40% [20–80]) was significantly lower (p < 0.001) than that in the young HS (80 [60–100]) (fig. 4) but there was no Aging and Esophageal Motility
1,200 1,000 800 600 400 200 0
Young HS
Elderly HS
Elderly RE
Fig. 3. The distal contractile integral (DCI) of primary peristalsis
in the young healthy subjects (HS), the elderly HS, and the elderly patients with reflux esophagitis (RE). Data are presented as median (interquartile range). n.s. = Not significant.
difference in the success rate of secondary peristalsis between the elderly HS and the elderly RE (40 [20–60]) (fig. 4). There was no difference in the DCI of secondary peristalsis between the young HS (714 mm Hg-s-cm [438– 1,121]) and the elderly HS (720 [393–1,601]) (fig. 5) but in the elderly RE (557 [329–684]) it was significantly lower (p = 0.0277) than in the elderly HS (fig. 5). Digestion 2015;91:181–186 DOI: 10.1159/000367650
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Basal LES Pressure There was no difference in the basal LES pressure between the young HS (10.6 mm Hg [8.0–13.4]) and the elderly HS (12.0 [9.4–14.7]) and between the elderly HS and the elderly RE (10.3 [8.1–17.2]) (fig. 1).
mm Hg-s-cm
1,400
Results
p < 0.001
n.s.
2,000
80
1,800 mm Hg-s-cm
70 60 50 40 30
1,600 1,400 1,200 1,000 800 600
20
400
10
200 0 Young HS
Elderly HS
Elderly RE
Young HS
Elderly HS
Elderly RE
Fig. 4. The success rate of secondary peristalsis in the young healthy
Fig. 5. The distal contractile integral (DCI) of secondary peristalsis
subjects (HS), the elderly HS, and the elderly patients with reflux esophagitis (RE). Data are presented as median (interquartile range). n.s. = Not significant.
in the young healthy subjects (HS), the elderly HS, and the elderly patients with reflux esophagitis (RE). Data are presented as median (interquartile range). n.s. = Not significant.
Discussion
New diagnostic criteria and classification (Chicago classification) of esophageal motility disorder for HRM with 36 channels, spaced at 1-cm intervals, were introduced [12]. In these criteria, the vigor of the esophageal contraction was estimated by the DCI (amplitude × duration × length [mm Hg-s-cm] of the distal esophageal contraction >20 mm Hg from proximal to distal pressure troughs). Peristaltic propagation was evaluated from the length of the peristaltic break, distal latency (DL), and contractile front velocity (CFV). In this study, esophageal manometry was carried out with a 21-channel manometric assembly, in which the side holes were spaced at 1-cm intervals from the proximal stomach to the distal esophagus, at 1 to 2-cm intervals at the middle esophagus and 2 to 3-cm intervals at the proximal esophagus. Although the manometry system we use with 21 channels is different from the HRM system with 36 channels, it is considered that the calculated value of the DCI is very similar to that of the HRM system with 36 channels. However, with regard to the success rate of peristalsis, we were unable to use the criteria of the Chicago classification because it was not possible to evaluate peristaltic breaks correctly in our manometry system. We therefore evaluated the success rate of peristalsis using previous criteria [9–11]. With regard to the effect of aging on esophageal motility, any differences between young HS and elderly HS 184
Digestion 2015;91:181–186 DOI: 10.1159/000367650
were compared but the lower success rate of secondary peristalsis in elderly HS was the only difference between these groups. First, this result suggested that if subjects have no reflux symptoms, such as heartburn, aging has no effect on basal LES pressure, the DCI, or the success rate of primary peristalsis. Second, that aging does contribute to a decrease in the success rate of secondary peristalsis. There has been only one study carried out on the effect of aging on secondary peristalsis where Ren et al. reported that the success rate of secondary peristalsis in elderly HS is significantly lower than in young HS [13]. Although their result is consistent with our result, their research was carried out on fewer subjects compared with ours. This study therefore is the first study, using a significant number of subjects simultaneously, in which the effects of aging on primary peristalsis, secondary peristalsis, and basal LES pressure were examined. There is less possibility that a motor nerve or the esophageal muscle itself would cause a decrease in the success rate of secondary peristalsis in elderly HS because there is no difference in the DCI between the young and elderly HS. We did consider however, that abnormal processing in the brain or a decrease in the perception of esophageal mucosa as a cause of the decrease in the success rate of secondary peristalsis in elderly HS. Meciano et al. reported that at necropsy, the number of neurons in the myenteric plexus of the esophagus in the elderly was less significant than in the young [14]. Kawami/Iwakiri/Sano/Tanaka/Sakamoto
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%
p = 0.0277
2,200
90
0
n.s.
2,400
100
This decrease in neurons in the elderly may be one of the causes of the decreased success rate of secondary peristalsis; however, it is not clear why only sensory neurons are impaired and motor neurons remain intact. Further study is required. In cases where acid reflux occurs while asleep, secondary peristalsis is very important in clearing refluxed acid from the esophagus into the stomach; however, the act of swallowing does not occur during sleep because saliva secretion is inhibited. If secondary peristalsis does not occur after nocturnal acid reflux, refluxed acid stays in the esophagus for a longer period of time and could possibly lead to excessive esophageal acid exposure, a cause of RE; therefore, even elderly people with no RE should avoid eating three hours before going to sleep. When considering the effect of acid reflux on esophageal motility, differences between elderly HS and elderly RE were compared. In this study, young patients with mild RE were not included as subjects, because generally speaking, the duration of the disease in young patients with RE is shorter than in elderly patients with RE and it is considered therefore, that the effect of acid reflux on esophageal motility in young patients with RE is less than in elderly patients with RE. In consideration of this possibility, the differences between elderly HS and elderly patients with RE were compared. The DCI of primary and secondary peristalsis in the elderly RE was significantly lower than in the elderly HS, which means that acid reflux itself may cause esophageal dysmotility. In the previous study, LES pressure, the success rate, and the amplitude of primary peristalsis in patients with RE increased after treatment, compared with
before treatment [15]. In some animal experiments, it has been reported that LES pressure or the amplitude of peristalsis decreased after experimental esophagitis [16– 18]. These results are consistent with our results; however, there is a contrary view. It is known that collagen disease is associated with a high prevalence of esophageal dysmotility [19] and it has been reported that many patients with collagen disease also have severe RE [20], which means that esophageal dysmotility causes RE. With regard to the cause of the decrease in the DCI in peristalsis in patients with RE, it is considered that proinflammatory cytokines IL-1β and IL-6 are produced as a result of esophagitis and these cytokines contribute to a decrease in an esophageal contraction by inhibiting the release of ACh from the myenteric neurons [21]. This may be the reason that esophageal motility decreases even if inflammation doesn’t reach the muscular layer. In conclusion, aging may be one of the causes for the decrease in the success rate of secondary peristalsis and as well acid reflux itself may cause a decrease in the DCI in primary and secondary peristalsis.
Disclosure Statement Dr. Iwakiri has received lecture fee from Takeda Pharmaceuticals Co. Ltd., and Eisai Co. Ltd. Dr. Sakamoto has served as a consultant and speaker for Astellas Pharma Inc., AstraZeneca, Eisai Co. Ltd., Otsuka Pharmaceuticals Co. Ltd., Pfizer Japan Inc., and Takeda Pharmaceuticals Co. Ltd. Dr. Sakamoto has also received grant/research support from Astellas Pharma Inc., AstraZeneca, Eisai Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Co. Ltd.
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