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doi:10.1111/jgh.12745
O R I G I N A L A RT I C L E
Atypical symptoms and health-related quality of life of patients with asymptomatic reflux esophagitis Toshihiko Tomita,* Toshinari Yasuda,† Hideo Oka,‡ Shuichi Terao,§ Eitastu Arai,¶ Tadayuki Oshima,* Hirokazu Fukui,* Kazutoshi Hori,* Jiro Watari* and Hiroto Miwa* *Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, †Hyogo Health Service Association, ‡Department of Internal Medicine, Amagasaki Central Hospital, §Department of Gastroenterology, Shinko Kakogawa Hospital, and ¶Department of Internal Medicine, Nishinomiya Kyoritsu Neurosurgical Hospital, Hyogo, Japan
Key words asymptomatic reflux esophagitis, atypical symptoms, HRQOL. Correspondence Hiroto Miwa, Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. Email: [email protected]
Abstract Background and Aim: Asymptomatic reflux esophagitis (RE) is simply regarded as RE without the typical reflux symptoms, but it is unknown whether patients with asymptomatic RE have atypical symptoms. The aim of this study was to examine the clinical characteristics and health-related quality of life (HRQOL) of patients with asymptomatic RE. Patients and Methods: Consecutive patients with RE were enrolled during January 2010 to August 2012, and of them, 41 who had taken acid-suppressing drugs were excluded, leaving 280 patients as the study group. The patients’ symptoms were evaluated using a self-completed questionnaire (modified Frequency Scale for the Symptoms of gastroesophageal reflux disease [FSSG]), as well as an HRQOL questionnaire (SF-8). We defined the typical symptoms of RE as heartburn and regurgitation. Asymptomatic RE was defined if the total symptom score was 0 or the minimum (1 point) for typical reflux symptoms in the modified FSSG. Results: Of the 280 RE patients, 71.8% (n = 201) were symptomatic and 28.2% (n = 79) were asymptomatic. The atypical symptom scores were significantly lower in asymptomatic RE (2.2 ± 2.2) than in symptomatic RE patients (6.9 ± 5.2) (P < 0.0001), and the HRQOL scores were significantly higher in asymptomatic RE than in symptomatic RE (P < 0.0001). Sleep was significantly less disturbed and chronic cough less frequent in asymptomatic RE than in symptomatic RE. Conclusion: Frequency and severity of atypical symptoms in patients with asymptomatic RE were significantly less than in patients with symptomatic RE, and the HRQOL score was significantly higher in those patients. These observations suggest a specific patient cohort that is truly unlikely to manifest symptoms.
Introduction Although the prevalence of gastroesophageal reflux disease (GERD) has been increasing in Japan from the 1990s to the 2010s,1 mainly because of the decreased rate of Helicobacter pylori infection and consequent increased gastric acid secretion,2,3 in approximately 90% of cases, the reflux esophagitis (RE) is endoscopically mild.1 GERD is generally diagnosed by esophagogastroduodenoscopy (EGD) and/or the presence of reflux symptoms, typically heartburn and regurgitation.4–11 However, some patients do not manifest symptoms and are regarded as having asymptomatic RE; that is, RE without the typical reflux symptoms. The prevalence of asymptomatic RE has been reported as approximately 11.6–73.8% of the Japanese population,12–16 but the clinical features have not been well elucidated and, importantly, it is still unknown whether such patients are really asymptomatic or they just do not complain about their symptoms even if they have some.
Previous studies have shown that RE patients not only have the typical reflux symptoms, but also atypical symptoms such as dysphagia and dyspepsia. However, little is known about whether patients with asymptomatic RE have these atypical reflux symptoms, nor is it known whether the health-related quality of life (HRQOL) of asymptomatic RE patients is significantly impaired compared with the general population. Therefore, in this study, we investigated the clinical characteristics and QOL of patients with asymptomatic RE with the aim of elucidating whether a specific patient cohort that is unlikely to develop esophageal symptoms does exist.
Patients and methods We conducted a cross-sectional study in which we enrolled 321 consecutive patients with RE (mean age, 56.7 ± 13.9; 240 men, 81 women) who had underwent EGD during January 2010 to August 2012. From these, 41 patients who had taken acid-suppressing
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 19–24 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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drugs (proton pump inhibitors or histamine-2 receptor antagonists) were excluded, leaving 280 patients (212 men, 68 women) as the study group. The patients’ symptoms were evaluated using a self-completed symptom questionnaire (see below), as well as a HRQOL questionnaire (SF-8) after endoscopic examination. Each patient’s clinical background was also recorded: age, sex, severity of esophagitis, grade of gastric mucosal atrophy, presence of Barrett’s epithelium, hiatus hernia, body mass index, drinking and smoking habits, and comorbidities such as hypertension, diabetes, and asthma. The severity of esophagitis was graded according to the Los Angeles classification (Grades A–D)17 and the extent of gastric mucosal atrophy was classified as closed (C type: C-1, C-2, C-3) or open (O type: O-1, O-2, O-3) using the system reported by Kimura and Takemoto.18 The presence or absence of Barrett’s epithelium was assessed in the area between the squamocolumnar junction and the esophagogastric junction, with the latter defined as the oral side of the gastric fold and the anal side of the palisade vessel.19 Hiatus hernia was endoscopically defined as > 2 cm separation of the upwardly displaced esophagogastric junction and the diaphragmatic impression.20 The patients were interviewed about their drinking and smoking habits. We defined the typical symptoms of RE as heartburn and regurgitation and used the modified Frequency Scale for the Symptoms of GERD (FSSG, Fig. 1).21,22 Atypical symptoms were also defined as the symptom except heartburn and regurgitation. The FSSG is classified into a total score, reflux score (questions 1, 4, 6, 7, 9, 10, 12) and dyspepsia score (questions 2, 3, 5, 8, 11). Patients were considered to be asymptomatic if their symptom score was zero or the minimum (1 point) for typical reflux symptoms.
Question
This study was approved by the Ethics Committee of the Hyogo College of Medicine. Written informed consent was given by all the patients prior to enrollment in the study. Statistical analysis. All results are expressed as mean ± standard deviation (SD). Mann–Whitney U-test, chisquare test, and Fisher’s exact test were used to compare groups. Statistical significance was defined as P < 0.05. Statistical analysis was performed using SPSS for Windows (Version 12.0; SPSS, Inc., Chicago, IL, USA).
Results Characteristics of patients with asymptomatic or symptomatic RE. With respect to background factors, the patients in the asymptomatic RE group were significantly older than those in the symptomatic esophagitis group, but there were no significant differences between the groups for any of the other characteristics (Table 1). Prevalence and atypical symptom score in patients with asymptomatic RE. The endoscopic grade was A in 176, B in 84, C in 18, and D in 2. Overall, 201 patients (71.8%) had symptomatic RE, and 79 (28.3%) were asymptomatic (Fig. 2). Of the patients with symptomatic RE, 91.0% (n = 183) had atypical or extraesophageal symptoms such as gastric dysmotility, globus sensation, and dysphagia, while 54.4% (n = 43) of the
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Figure 1 Modified Frequency Scale for the Symptom of Gastroesophageal Reflux Disease with two added questions (sleep disturbance and cough frequency). Typical symptoms relate to questions 1, 6, 10, 12, and atypical symptoms to questions 2–5, 7–9, and 11, 13, 14.
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Table 1
Asymptomatic reflux esophagitis
Characteristics of the study patients with reflux esophagitis (RE)
Age (year ± SD) Sex (M/F) Severity of esophagitis† (A/B/C/D) Mucosal atrophy‡ (C-0/C-1/C-2/C-3/O-1/O-2/O-3) Barrett’s epithelium Hiatus hernia (+/−) Body mass index Drinking habit (+/−) Smoking habit (+/−) Hypertension (+/−) Diabetes mellitus (+/−) Asthma (+/−)
Asymptomatic RE (n = 79)
Symptomatic RE (n = 201)
P-value
59.7 ± 14.6 62/17 55/20/4/0 19/27/16/5/6/4/2 32.9% (24/79) 59.5% (47/79) 23.7 ± 7.9 40.5% (32/79) 31.6% (25/79) 25.3% (20/79) 16.5% (13/79) 3.8% (3/79)
55.7 ± 13.5 150/51 121/64/14/2 64/69/35/10/12/7/4 24.9% (50/201) 67.7% (136/201) 24.0 ± 4.0 50.7% (102/201) 34% (67/201) 27.9% (56/201) 12.9% (26/201) 2.0% (4/201)
< 0.05 NS NS NS NS NS NS NS NS NS NS NS
†
Los Angeles classification. Criteria of Kimura and Takemoto.18 NS, not significant.
Number of patients
‡
60
28.3%㩷 (79/280)
P < 0.0001
50
䋨n=280 䋩
40 30 71.7%㩷 (201/280)
20 10 0 0 1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 Sum of modified FSSG scores
Figure 2 Sum of typical reflux symptom scores showing that overall, 71.7% of the study patients had symptomatic reflux esophagitis and 28.3% were asymptomatic. FSSG, frequency of scale for the symptoms of GERD.
Asymptomatic RE
Symptomatic RE
Figure 3 Total scores for atypical symptoms are significantly lower in patients with asymptomatic reflux esophagitis (RE) than in those with symptomatic RE.
patients with asymptomatic RE had atypical symptoms. The mean reflux and dyspepsia scores were significantly lower in the asymptomatic RE (0.15 ± 0.15, 0.3 ± 0.12) than in the symptomatic RE group (1.0 ± 0.5, 1.0 ± 0.5) (P < 0.01). The total scores for atypical symptoms were significantly lower in the asymptomatic RE (mean ± SD; 2.2 ± 2.2) than in the symptomatic RE group (6.9 ± 5.2) (P < 0.0001) (Fig. 3).
SF-8 score in patients with asymptomatic or symptomatic RE. The HRQOL scores in six of eight SF8 domains were significantly higher in asymptomatic RE than in symptomatic RE; however, two HRQOL items (physical functioning and role physical) did not significantly differ between the two groups. Mental component summary was significantly higher in asymptomatic RE (50.0 ± 6.1) than in symptomatic RE (47.5 ± 7.5) (P < 0.01) (Fig. 5).
Comparison of sleep disturbance and cough frequency in patients with asymptomatic or symptomatic RE. Sleep was significantly less disturbed in asymptomatic RE (1.1 ± 1.2) than in symptomatic RE patients (1.6 ± 1.3) (P < 0.01). Chronic cough was also significantly less frequent in asymptomatic RE (0.6 ± 1.1) than in symptomatic RE (0.8 ± 1.0) (P < 0.05) (Fig. 4).
Discussion In the actual clinical setting, endoscopists may coincidentally encounter cases of asymptomatic RE because generally patients with this disease will not visit hospital. To date, there have been several reports of the prevalence of asymptomatic RE, but results are inconsistent, ranging from 4.3% to 73.8%.12–16,23–26 In this
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 19–24 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Sleep disturbance P < 0.01
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Cough frequency P < 0.05
Asymptomatic RE
Symptomatic RE
Figure 4 Sleep disturbance (Left) and cough frequency (Right) scores in patients with asymptomatic or symptomatic reflux esophagitis (RE). Sleep was significantly less disturbed and chronic cough was less frequent in asymptomatic RE than in symptomatic RE.
MCS
PCS
P < 0.01
NS
Asymptomatic RE
Symptomatic RE
Asymptomatic RE
Symptomatic RE
Figure 5 Health-related quality of life (HRQOL) scores in patients with asymptomatic or symptomatic reflux esophagitis (RE). The mental component summary was significantly higher in asymptomatic RE than in symptomatic RE. MCS, mental component summary; NS, not significant; PCS, physical component summary.
study, the prevalence of asymptomatic RE was 28.3%. One reason for this discrepancy in prevalence is differences in the definition of asymptomatic RE. Mishima et al. reported a very high prevalence of 73.8%, and they defined asymptomatic RE as the quality of life and utility evaluation survey technology (QUEST) score < 5.16,27 Other Japanese studies have reported from 12.0% to 58.8% of endoscopically diagnosed RE, but the questionnaire used in those studies also varied.12–16 Another possible reason is differences in the backgrounds of the study subjects; some studies investigated healthy subjects undergoing regular health checkups,13 and other studies examined patients who visited hospital.12,14–16 It has been recently revealed that patients with RE usually have dyspeptic symptoms such as dysphagia and dysmotility, but few have investigated the presence of these atypical symptoms in asymptomatic RE patients. We used the FSSG questionnaire in this study because it evaluates both the typical and atypical reflux symptoms.21,22 Nagahara et al. reported a prevalence of asymptomatic RE of 11.6% using the FSSG scale,14 which was lower than in the previous studies because they defined asymptomatic RE as a total FSSG score of zero. In contrast, we considered patients were asymptomatic if their score for typical symptoms was zero or the minimum (1 point), so although the prevalence in our study was 28.2%, it would have been 6.5% if we had used the criteria of 22
Nagahara et al., which suggests that asymptomatic RE is not a rare disease. Many studies have reported that the HRQOL in patients with GERD is significantly impaired compared with that of the general population.28–31 Ameliorating the symptoms of GERD is associated with improved HRQOL. In this study, the mean HRQOL scores for most of the SF-8 domains were significantly higher in asymptomatic RE than in symptomatic RE. The HRQOL scores of asymptomatic RE patients were similar to the national standard. The patients with asymptomatic RE did not have any unpleasant feelings, despite having esophageal mucosal injury, which suggests that they do not report symptoms because they really do not feel symptoms, not because they keep silent about them. Moreover, in this study, there was no significant differences in the degree of severity of esophagitis between the two groups. Unfortunately we have no data regarding the acid secretion between the two groups. However, severity of esphageal mucosal damage is known to be associated with acid exporsure time of the esophagis. In other words, intra-esophageal acid exposure time determines severity of the esophagitis. From this point of view, it is speculated that there may be no difference of acid secretion between these two groups. In addition, disease severity is not necessarily correlated to severity of GERD symptoms in patients with reflux esophagitis.32 This finding suggests the reason why the patients did not feel symptoms may not be explained by the amount of the intra-esophageal acid exposure. The pathogenesis of asymptomatic RE is unknown. With respect to background factors, patients in the asymptomatic RE group were significantly older than those in the symptomatic RE group in the present study. Regarding age, we recently reported that the thresholds of esophageal visceral chemosensitivity and mechanosensitivity were significantly inversely correlated with age.33 Another report also showed that the esophageal perception threshold increases with age.34 In addition, some have reported that the ratio of asymptomatic RE patients was greater among the elderly.14,35,36 Taken together, the findings suggest decreased esophageal sensitivity is involved in the pathogenesis of asymptomatic RE. Sleep disturbance often occurs with GERD.37–38 Exposure of the esophagus to acid at night may evoke substantial symptoms, which disturbs the patient’s sleep. Use of a proton pump inhibitor has been found to reduce nighttime heartburn and GERDrelated sleep disturbance, and improve sleep quality and work productivity.38 In this study, we found that sleep was significantly less disturbed in asymptomatic RE than in symptomatic RE, which suggests that asymptomatic RE patients do not experience nocturnal symptoms and thus have a good sleep. In this study, chronic cough was also significantly less frequent in asymptomatic RE than in symptomatic RE. It is well known that GERD often causes nonspecific chronic cough,39–42 although the mechanism is not well elucidated, and it is not known why cough is less frequent in asymptomatic RE when the acid exposure time is considered to be similar to that of symptomatic RE patients. However, if chronic cough is caused by a sensitive esophageal neural network, including esophageal vagal reflux, cough may be less frequent in asymptomatic RE patients because their neural function is possibly impaired. Another possibility is asymptomatic RE patients have less nighttime acid reflux, but their
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intraesophageal pH profiles have not been investigated and should be done in a future study. In conclusion, to the best of our knowledge, this is the first cross-sectional study to evaluate the frequency and severity of atypical symptoms in patients with asymptomatic RE, both of which were significantly less than in symptomatic RE patients. The HRQOL score was also significantly higher in such patients. These observations suggest a specific patient cohort that is truly unlikely to manifest symptoms. In conclusion, the frequency and severity of atypical symptoms in patients with asymptomatic RE were significantly less than those in symptomatic RE patients. The HRQOL score was also significantly higher in such patients. These observations demonstrated that asymptomatic RE is really asymptomatic, which suggests presence of a specific patient cohort that is truly unlikely to manifest symptoms.
References 1 Fujiwara Y, Arakawa T. Epidemiology and clinical characteristics of GERD in the Japanese population. J. Gastroenterol. 2009; 44: 518–34. 2 Kinoshita Y, Kawanami C, Kishi K et al. Helicobacter pylori independent chronological change in gastric acid secretion in the Japanese. Gut 1997; 41: 452–8. 3 Sugiyama T, Nishikawa K, Komatsu Y et al. Attributable risk of H. pylori in peptic ulcer disease: does declining prevalence of infection in general population explain increasing frequency of non-H. pylori ulcers? Dig. Dis. Sci. 2001; 46: 307–10. 4 Okamoto K, Iwakiri R, Mori M et al. Clinical symptoms in endoscopic reflux esophagitis: evaluation in 8031 adult subjects. Dig. Dis. Sci. 2003; 48: 2237–41. 5 Ohara S, Kouzu T, Kawano T et al. Nationwide epidemiological survey regarding heartburn and reflux esophagitis in Japanese. Nihon Shokakibyo Gakkai Zasshi 2005; 102: 1010–24. (In Japanese.) 6 Sakaguchi M, Oka H, Hashimoto T et al. Obesity as a risk factor for GERD in Japan. J. Gastroenterol. 2008; 43: 57–62. 7 Stanghellini V. Three-month prevalence rates of gastrointestinal symptoms and the influence of demographic factors: results from the Domestic/International Gastroenterology Surveillance Study (DIGEST). Scand. J. Gastroenterol. 1999; 231 (Suppl.): 20–8. 8 Fujiwara Y, Higuchi K, Watanabe Y et al. Prevalence of gastroesophageal reflux disease and gastroesophageal reflux disease symptoms in Japan. J. Gastroenterol. Hepatol. 2005; 20: 26–9. 9 Watanabe Y, Fujiwara Y, Shiba M et al. Cigarette smoking and alcohol consumption associated with gastro-oesophageal reflux disease in Japanese men. Scand. J. Gastroenterol. 2003; 38: 807–11. 10 Kubota E, Tanida S, Sasaki M et al. Contribution of Helicobacter pylori infection and obesity on heartburn in a Japanese population. J. Clin. Biochem. Nutr. 2006; 39: 168–73. 11 Yamagishi H, Koike T, Ohara S et al. Prevalence of gastroesophageal reflux symptoms in a large unselected general population in Japan. World J. Gastroenterol. 2008; 14: 1358–64. 12 Nozu T, Komiyama H. Clinical characteristics of asymptomatic esophagitis. J. Gastroenterol. 2008; 43: 27–31. 13 Murao T, Sakurai K, Mihara S et al. Lifestyle change influences on GERD in Japan: a study of participants in a health examination program. Dig. Dis. Sci. 2011; 56: 2857–64. 14 Nagahara A, Hojo M, Asaoka D et al. Clinical feature of asymptomatic reflux esophagitis in patients who underwent upper gastrointestinal endoscopy. J. Gastroenterol. Hepatol. 2012; 27 (Suppl. 3): 53–7.
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15 Yagi N, Arai M, Fujimoto S. Importance of lifestyle advice in the management of endoscopically negative gastroesophageal reflux disease patients in Japan. Shoukakika 2006; 43: 194–201. (In Japanese.) 16 Mishima I, Adachi K, Arima N et al. Prevalence of endoscopically negative and positive gastroesophageal reflux disease in the Japanese. Scand. J. Gastroenterol. 2005; 40: 1005–9. 17 Lundell LR, Dent J, Bennett JR et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999; 45: 172–80. 18 Kimura K, Takemoto T. An endoscopic recognition of the atrophic border and its significance in chronic gastritis. Endoscopy 1969; 3: 87–97. 19 Fujiwara Y, Higuchi K, Shiba M et al. Association between gastroesophageal flap valve, reflux esophagitis, Barrett’s epithelium, and atrophic gastritis assessed by endoscopy in Japanese patients. J. Gastroenterol. 2003; 38: 533–9. 20 Van Herwaarden MA, Samsom M, Smout AJ. The role of hiatus hernia in gastro-oesophageal reflux disease. Eur. J. Gastroenterol. Hepatol. 2004; 16: 831–5. 21 Kusano M, Shimoyama Y, Sugimoto S et al. Development and evaluation of FSSG: frequency scale for the symptoms of GERD. J. Gastroenterol. 2004; 39: 888–91. 22 Shimoyama Y, Kusano M, Sugimoto S et al. Diagnosis of gastroesophageal reflux disease using a new questionnaire. J. Gastroenterol. Hepatol. 2005; 20: 643–7. 23 Fass R, Dickman R. Clinical consequences of silent gastroesophageal reflux disease. Curr. Gastroenterol. Rep. 2006; 8: 195–201. 24 Cho JH, Kim HM, Ko GJ et al. Old age and male sex are associated with increased risk of asymptomatic erosive esophagitis: analysis of data from local health examinations by the Korean National Health Insurance Corporation. J. Gastroenterol. Hepatol. 2011; 26: 1034–8. 25 Peng S, Cui Y, Xiao YL et al. Prevalence of erosive esophagitis and Barrett’s esophagus in the adult Chinese population. Endoscopy 2009; 41: 1011–7. 26 Wang FW, Tu MS, Chuang HY et al. Erosive esophagitis in asymptomatic subjects: risk factors. Dig. Dis. Sci. 2010; 55: 1320–4. 27 Carlsson R, Dent J, Bolling-Sternevald E et al. The usefulness of a structured questionnaire in the assessment of symptomatic gastroesophageal reflux disease. Scand. J. Gastroenterol. 1998; 33: 1023–9. 28 Prasad M, Rentz AM, Revicki DA. The impact of treatment for gastro-oesophageal reflux disease on health-related quality of life: a literature review. Pharmacoeconomics 2003; 21: 769–90. 29 Eslick GD, Talley NJ. Gastroesophageal reflux disease (GERD): risk factors, and impact on quality of life-a population-based study. J. Clin. Gastroenterol. 2009; 43: 111–7. 30 Leplège A, Mackenzie-Schliacowsky N, Eacute Cosse E et al. Quality of life scale and impact of a topical treatment on symptoms of gastro-esophageal reflux without severe esophagitis. Gastroenterol. Clin. Biol. 2005; 29: 676–81. 31 Mine S, Iida T, Tabata T et al. Management of symptoms in step-down therapy of gastroesophageal reflux disease. J. Gastroenterol. Hepatol. 2005; 20: 1365–70. 32 Johnson DA, Fennerty MB. Heartburn severity underestimates erosive esophagitis severity in elderly patients with gastroesophageal reflux disease. Gastroenterology 2004; 126: 660–4. 33 Yamasaki T, Oshima T, Tomita T et al. Effect of age and correlation between esophageal visceral chemosensitivity and mechanosensitivity in healthy Japanese subjects. J. Gastroenterol. 2013; 48: 360–5.
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34 Lasch H, Castell DO, Castell JA. Evidence for diminished visceral pain with aging: studies using graded intraesophageal balloon distension. Am. J. Physiol. 1997; 272: G1–3. 35 Urita Y, Miki K. Reflux esophagitis in the elderly. Clinica 1998; 25: 257–61. (In Japanese.) 36 Tanimura H, Kubo M, Kawano S. Clinical study of reflux esophagitis in the elderly. Ther. Res. 1999; 20: 2297–9. (In Japanese.) 37 Suganuma N, Shigedo Y, Adachi H et al. Association of gastroesophageal reflux disease with weight gain and apnea, and their disturbance on sleep. Psychiatry Clin. Neurosci. 2001; 55: 255–6. 38 Janson C, Gislason T, De Backer W et al. Daytime sleepiness, snoring and gastro-oesophageal reflux amongst young adults in three European countries. J. Intern. Med. 1995; 237: 277–85.
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39 Johnson DA, Orr WC, Crawley JA et al. Effect of esomeprazole on nighttime heartburn and sleep quality in patients with GERD: a randomized, placebo-controlled trial. Am. J. Gastroenterol. 2005; 100: 1914–22. 40 Ing AJ, Ngu MC, Breslin AB. Pathogenesis of chronic persistent cough associated with gastroesophageal reflux. Am. J. Respir. Crit. Care Med. 1994; 149: 160–7. 41 Chang AB, Lasserson TJ, Kiljander TO et al. Systematic review and meta-analysis of randomised controlled trials of gastro-oesophageal reflux interventions for chronic cough associated with gastro-oesophageal reflux. BMJ 2006; 332: 11–7. 42 Chang AB, Lasserson TJ, Gaffney J et al. Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults. Cochrane Database Syst. Rev. 2011; (1): Review.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 19–24 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
doi:10.1111/jgh.12745
O R I G I N A L A RT I C L E
Atypical symptoms and health-related quality of life of patients with asymptomatic reflux esophagitis Toshihiko Tomita,* Toshinari Yasuda,† Hideo Oka,‡ Shuichi Terao,§ Eitastu Arai,¶ Tadayuki Oshima,* Hirokazu Fukui,* Kazutoshi Hori,* Jiro Watari* and Hiroto Miwa* *Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, †Hyogo Health Service Association, ‡Department of Internal Medicine, Amagasaki Central Hospital, §Department of Gastroenterology, Shinko Kakogawa Hospital, and ¶Department of Internal Medicine, Nishinomiya Kyoritsu Neurosurgical Hospital, Hyogo, Japan
Key words asymptomatic reflux esophagitis, atypical symptoms, HRQOL. Correspondence Hiroto Miwa, Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. Email: [email protected]
Abstract Background and Aim: Asymptomatic reflux esophagitis (RE) is simply regarded as RE without the typical reflux symptoms, but it is unknown whether patients with asymptomatic RE have atypical symptoms. The aim of this study was to examine the clinical characteristics and health-related quality of life (HRQOL) of patients with asymptomatic RE. Patients and Methods: Consecutive patients with RE were enrolled during January 2010 to August 2012, and of them, 41 who had taken acid-suppressing drugs were excluded, leaving 280 patients as the study group. The patients’ symptoms were evaluated using a self-completed questionnaire (modified Frequency Scale for the Symptoms of gastroesophageal reflux disease [FSSG]), as well as an HRQOL questionnaire (SF-8). We defined the typical symptoms of RE as heartburn and regurgitation. Asymptomatic RE was defined if the total symptom score was 0 or the minimum (1 point) for typical reflux symptoms in the modified FSSG. Results: Of the 280 RE patients, 71.8% (n = 201) were symptomatic and 28.2% (n = 79) were asymptomatic. The atypical symptom scores were significantly lower in asymptomatic RE (2.2 ± 2.2) than in symptomatic RE patients (6.9 ± 5.2) (P < 0.0001), and the HRQOL scores were significantly higher in asymptomatic RE than in symptomatic RE (P < 0.0001). Sleep was significantly less disturbed and chronic cough less frequent in asymptomatic RE than in symptomatic RE. Conclusion: Frequency and severity of atypical symptoms in patients with asymptomatic RE were significantly less than in patients with symptomatic RE, and the HRQOL score was significantly higher in those patients. These observations suggest a specific patient cohort that is truly unlikely to manifest symptoms.
Introduction Although the prevalence of gastroesophageal reflux disease (GERD) has been increasing in Japan from the 1990s to the 2010s,1 mainly because of the decreased rate of Helicobacter pylori infection and consequent increased gastric acid secretion,2,3 in approximately 90% of cases, the reflux esophagitis (RE) is endoscopically mild.1 GERD is generally diagnosed by esophagogastroduodenoscopy (EGD) and/or the presence of reflux symptoms, typically heartburn and regurgitation.4–11 However, some patients do not manifest symptoms and are regarded as having asymptomatic RE; that is, RE without the typical reflux symptoms. The prevalence of asymptomatic RE has been reported as approximately 11.6–73.8% of the Japanese population,12–16 but the clinical features have not been well elucidated and, importantly, it is still unknown whether such patients are really asymptomatic or they just do not complain about their symptoms even if they have some.
Previous studies have shown that RE patients not only have the typical reflux symptoms, but also atypical symptoms such as dysphagia and dyspepsia. However, little is known about whether patients with asymptomatic RE have these atypical reflux symptoms, nor is it known whether the health-related quality of life (HRQOL) of asymptomatic RE patients is significantly impaired compared with the general population. Therefore, in this study, we investigated the clinical characteristics and QOL of patients with asymptomatic RE with the aim of elucidating whether a specific patient cohort that is unlikely to develop esophageal symptoms does exist.
Patients and methods We conducted a cross-sectional study in which we enrolled 321 consecutive patients with RE (mean age, 56.7 ± 13.9; 240 men, 81 women) who had underwent EGD during January 2010 to August 2012. From these, 41 patients who had taken acid-suppressing
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 19–24 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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drugs (proton pump inhibitors or histamine-2 receptor antagonists) were excluded, leaving 280 patients (212 men, 68 women) as the study group. The patients’ symptoms were evaluated using a self-completed symptom questionnaire (see below), as well as a HRQOL questionnaire (SF-8) after endoscopic examination. Each patient’s clinical background was also recorded: age, sex, severity of esophagitis, grade of gastric mucosal atrophy, presence of Barrett’s epithelium, hiatus hernia, body mass index, drinking and smoking habits, and comorbidities such as hypertension, diabetes, and asthma. The severity of esophagitis was graded according to the Los Angeles classification (Grades A–D)17 and the extent of gastric mucosal atrophy was classified as closed (C type: C-1, C-2, C-3) or open (O type: O-1, O-2, O-3) using the system reported by Kimura and Takemoto.18 The presence or absence of Barrett’s epithelium was assessed in the area between the squamocolumnar junction and the esophagogastric junction, with the latter defined as the oral side of the gastric fold and the anal side of the palisade vessel.19 Hiatus hernia was endoscopically defined as > 2 cm separation of the upwardly displaced esophagogastric junction and the diaphragmatic impression.20 The patients were interviewed about their drinking and smoking habits. We defined the typical symptoms of RE as heartburn and regurgitation and used the modified Frequency Scale for the Symptoms of GERD (FSSG, Fig. 1).21,22 Atypical symptoms were also defined as the symptom except heartburn and regurgitation. The FSSG is classified into a total score, reflux score (questions 1, 4, 6, 7, 9, 10, 12) and dyspepsia score (questions 2, 3, 5, 8, 11). Patients were considered to be asymptomatic if their symptom score was zero or the minimum (1 point) for typical reflux symptoms.
Question
This study was approved by the Ethics Committee of the Hyogo College of Medicine. Written informed consent was given by all the patients prior to enrollment in the study. Statistical analysis. All results are expressed as mean ± standard deviation (SD). Mann–Whitney U-test, chisquare test, and Fisher’s exact test were used to compare groups. Statistical significance was defined as P < 0.05. Statistical analysis was performed using SPSS for Windows (Version 12.0; SPSS, Inc., Chicago, IL, USA).
Results Characteristics of patients with asymptomatic or symptomatic RE. With respect to background factors, the patients in the asymptomatic RE group were significantly older than those in the symptomatic esophagitis group, but there were no significant differences between the groups for any of the other characteristics (Table 1). Prevalence and atypical symptom score in patients with asymptomatic RE. The endoscopic grade was A in 176, B in 84, C in 18, and D in 2. Overall, 201 patients (71.8%) had symptomatic RE, and 79 (28.3%) were asymptomatic (Fig. 2). Of the patients with symptomatic RE, 91.0% (n = 183) had atypical or extraesophageal symptoms such as gastric dysmotility, globus sensation, and dysphagia, while 54.4% (n = 43) of the
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Figure 1 Modified Frequency Scale for the Symptom of Gastroesophageal Reflux Disease with two added questions (sleep disturbance and cough frequency). Typical symptoms relate to questions 1, 6, 10, 12, and atypical symptoms to questions 2–5, 7–9, and 11, 13, 14.
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Table 1
Asymptomatic reflux esophagitis
Characteristics of the study patients with reflux esophagitis (RE)
Age (year ± SD) Sex (M/F) Severity of esophagitis† (A/B/C/D) Mucosal atrophy‡ (C-0/C-1/C-2/C-3/O-1/O-2/O-3) Barrett’s epithelium Hiatus hernia (+/−) Body mass index Drinking habit (+/−) Smoking habit (+/−) Hypertension (+/−) Diabetes mellitus (+/−) Asthma (+/−)
Asymptomatic RE (n = 79)
Symptomatic RE (n = 201)
P-value
59.7 ± 14.6 62/17 55/20/4/0 19/27/16/5/6/4/2 32.9% (24/79) 59.5% (47/79) 23.7 ± 7.9 40.5% (32/79) 31.6% (25/79) 25.3% (20/79) 16.5% (13/79) 3.8% (3/79)
55.7 ± 13.5 150/51 121/64/14/2 64/69/35/10/12/7/4 24.9% (50/201) 67.7% (136/201) 24.0 ± 4.0 50.7% (102/201) 34% (67/201) 27.9% (56/201) 12.9% (26/201) 2.0% (4/201)
< 0.05 NS NS NS NS NS NS NS NS NS NS NS
†
Los Angeles classification. Criteria of Kimura and Takemoto.18 NS, not significant.
Number of patients
‡
60
28.3%㩷 (79/280)
P < 0.0001
50
䋨n=280 䋩
40 30 71.7%㩷 (201/280)
20 10 0 0 1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 Sum of modified FSSG scores
Figure 2 Sum of typical reflux symptom scores showing that overall, 71.7% of the study patients had symptomatic reflux esophagitis and 28.3% were asymptomatic. FSSG, frequency of scale for the symptoms of GERD.
Asymptomatic RE
Symptomatic RE
Figure 3 Total scores for atypical symptoms are significantly lower in patients with asymptomatic reflux esophagitis (RE) than in those with symptomatic RE.
patients with asymptomatic RE had atypical symptoms. The mean reflux and dyspepsia scores were significantly lower in the asymptomatic RE (0.15 ± 0.15, 0.3 ± 0.12) than in the symptomatic RE group (1.0 ± 0.5, 1.0 ± 0.5) (P < 0.01). The total scores for atypical symptoms were significantly lower in the asymptomatic RE (mean ± SD; 2.2 ± 2.2) than in the symptomatic RE group (6.9 ± 5.2) (P < 0.0001) (Fig. 3).
SF-8 score in patients with asymptomatic or symptomatic RE. The HRQOL scores in six of eight SF8 domains were significantly higher in asymptomatic RE than in symptomatic RE; however, two HRQOL items (physical functioning and role physical) did not significantly differ between the two groups. Mental component summary was significantly higher in asymptomatic RE (50.0 ± 6.1) than in symptomatic RE (47.5 ± 7.5) (P < 0.01) (Fig. 5).
Comparison of sleep disturbance and cough frequency in patients with asymptomatic or symptomatic RE. Sleep was significantly less disturbed in asymptomatic RE (1.1 ± 1.2) than in symptomatic RE patients (1.6 ± 1.3) (P < 0.01). Chronic cough was also significantly less frequent in asymptomatic RE (0.6 ± 1.1) than in symptomatic RE (0.8 ± 1.0) (P < 0.05) (Fig. 4).
Discussion In the actual clinical setting, endoscopists may coincidentally encounter cases of asymptomatic RE because generally patients with this disease will not visit hospital. To date, there have been several reports of the prevalence of asymptomatic RE, but results are inconsistent, ranging from 4.3% to 73.8%.12–16,23–26 In this
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 19–24 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Sleep disturbance P < 0.01
Symptomatic RE
Asymptomatic RE
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Cough frequency P < 0.05
Asymptomatic RE
Symptomatic RE
Figure 4 Sleep disturbance (Left) and cough frequency (Right) scores in patients with asymptomatic or symptomatic reflux esophagitis (RE). Sleep was significantly less disturbed and chronic cough was less frequent in asymptomatic RE than in symptomatic RE.
MCS
PCS
P < 0.01
NS
Asymptomatic RE
Symptomatic RE
Asymptomatic RE
Symptomatic RE
Figure 5 Health-related quality of life (HRQOL) scores in patients with asymptomatic or symptomatic reflux esophagitis (RE). The mental component summary was significantly higher in asymptomatic RE than in symptomatic RE. MCS, mental component summary; NS, not significant; PCS, physical component summary.
study, the prevalence of asymptomatic RE was 28.3%. One reason for this discrepancy in prevalence is differences in the definition of asymptomatic RE. Mishima et al. reported a very high prevalence of 73.8%, and they defined asymptomatic RE as the quality of life and utility evaluation survey technology (QUEST) score < 5.16,27 Other Japanese studies have reported from 12.0% to 58.8% of endoscopically diagnosed RE, but the questionnaire used in those studies also varied.12–16 Another possible reason is differences in the backgrounds of the study subjects; some studies investigated healthy subjects undergoing regular health checkups,13 and other studies examined patients who visited hospital.12,14–16 It has been recently revealed that patients with RE usually have dyspeptic symptoms such as dysphagia and dysmotility, but few have investigated the presence of these atypical symptoms in asymptomatic RE patients. We used the FSSG questionnaire in this study because it evaluates both the typical and atypical reflux symptoms.21,22 Nagahara et al. reported a prevalence of asymptomatic RE of 11.6% using the FSSG scale,14 which was lower than in the previous studies because they defined asymptomatic RE as a total FSSG score of zero. In contrast, we considered patients were asymptomatic if their score for typical symptoms was zero or the minimum (1 point), so although the prevalence in our study was 28.2%, it would have been 6.5% if we had used the criteria of 22
Nagahara et al., which suggests that asymptomatic RE is not a rare disease. Many studies have reported that the HRQOL in patients with GERD is significantly impaired compared with that of the general population.28–31 Ameliorating the symptoms of GERD is associated with improved HRQOL. In this study, the mean HRQOL scores for most of the SF-8 domains were significantly higher in asymptomatic RE than in symptomatic RE. The HRQOL scores of asymptomatic RE patients were similar to the national standard. The patients with asymptomatic RE did not have any unpleasant feelings, despite having esophageal mucosal injury, which suggests that they do not report symptoms because they really do not feel symptoms, not because they keep silent about them. Moreover, in this study, there was no significant differences in the degree of severity of esophagitis between the two groups. Unfortunately we have no data regarding the acid secretion between the two groups. However, severity of esphageal mucosal damage is known to be associated with acid exporsure time of the esophagis. In other words, intra-esophageal acid exposure time determines severity of the esophagitis. From this point of view, it is speculated that there may be no difference of acid secretion between these two groups. In addition, disease severity is not necessarily correlated to severity of GERD symptoms in patients with reflux esophagitis.32 This finding suggests the reason why the patients did not feel symptoms may not be explained by the amount of the intra-esophageal acid exposure. The pathogenesis of asymptomatic RE is unknown. With respect to background factors, patients in the asymptomatic RE group were significantly older than those in the symptomatic RE group in the present study. Regarding age, we recently reported that the thresholds of esophageal visceral chemosensitivity and mechanosensitivity were significantly inversely correlated with age.33 Another report also showed that the esophageal perception threshold increases with age.34 In addition, some have reported that the ratio of asymptomatic RE patients was greater among the elderly.14,35,36 Taken together, the findings suggest decreased esophageal sensitivity is involved in the pathogenesis of asymptomatic RE. Sleep disturbance often occurs with GERD.37–38 Exposure of the esophagus to acid at night may evoke substantial symptoms, which disturbs the patient’s sleep. Use of a proton pump inhibitor has been found to reduce nighttime heartburn and GERDrelated sleep disturbance, and improve sleep quality and work productivity.38 In this study, we found that sleep was significantly less disturbed in asymptomatic RE than in symptomatic RE, which suggests that asymptomatic RE patients do not experience nocturnal symptoms and thus have a good sleep. In this study, chronic cough was also significantly less frequent in asymptomatic RE than in symptomatic RE. It is well known that GERD often causes nonspecific chronic cough,39–42 although the mechanism is not well elucidated, and it is not known why cough is less frequent in asymptomatic RE when the acid exposure time is considered to be similar to that of symptomatic RE patients. However, if chronic cough is caused by a sensitive esophageal neural network, including esophageal vagal reflux, cough may be less frequent in asymptomatic RE patients because their neural function is possibly impaired. Another possibility is asymptomatic RE patients have less nighttime acid reflux, but their
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intraesophageal pH profiles have not been investigated and should be done in a future study. In conclusion, to the best of our knowledge, this is the first cross-sectional study to evaluate the frequency and severity of atypical symptoms in patients with asymptomatic RE, both of which were significantly less than in symptomatic RE patients. The HRQOL score was also significantly higher in such patients. These observations suggest a specific patient cohort that is truly unlikely to manifest symptoms. In conclusion, the frequency and severity of atypical symptoms in patients with asymptomatic RE were significantly less than those in symptomatic RE patients. The HRQOL score was also significantly higher in such patients. These observations demonstrated that asymptomatic RE is really asymptomatic, which suggests presence of a specific patient cohort that is truly unlikely to manifest symptoms.
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39 Johnson DA, Orr WC, Crawley JA et al. Effect of esomeprazole on nighttime heartburn and sleep quality in patients with GERD: a randomized, placebo-controlled trial. Am. J. Gastroenterol. 2005; 100: 1914–22. 40 Ing AJ, Ngu MC, Breslin AB. Pathogenesis of chronic persistent cough associated with gastroesophageal reflux. Am. J. Respir. Crit. Care Med. 1994; 149: 160–7. 41 Chang AB, Lasserson TJ, Kiljander TO et al. Systematic review and meta-analysis of randomised controlled trials of gastro-oesophageal reflux interventions for chronic cough associated with gastro-oesophageal reflux. BMJ 2006; 332: 11–7. 42 Chang AB, Lasserson TJ, Gaffney J et al. Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults. Cochrane Database Syst. Rev. 2011; (1): Review.
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