SYSTEMATIC REVIEWS AND META-ANALYSES. Systematic Review: Patterns of Reflux-Induced Symptoms and Esophageal Endoscopic Findings in Large-Scale Surveys

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: SYSTEMATIC REVIEWS AND META-ANALYSES Systematic Review: Patterns of Reflux-Induced Symptoms and Esophageal Endoscopic Findings in Large-Scale Surveys Fasiha Kanwal, Section Editor JOHN DENT,* ANJA BECHER, JOSEPH SUNG, DUOWU ZOU, LARS AGRÉUS, and FRANCO BAZZOLI # *Departt of Gastroenterology and Hepatology, Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia; Research Evaluation Unit, Oxford PharmaGenesis Ltd, Oxford, United Kingdom; Institute of Digestive Diseases, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China; Departt of Gastroenterology, Changhai Hospital, Secondary Military Medical University, Shanghai, China; Center for Family and Community Medicine, Departt of Neurobiology, Caring Sciences and Society, Karolinska Institute, Stockholm, Sweden; and # Departt of Clinical Medicine, University of Bologna, Bologna, Italy BACKGROUND & AIMS: This systematic review assesses findings of endoscopic surveys in the general population with regard to gastroesophageal reflux disease (GERD). METHODS: Systematic searches were conducted in PubMed and EMBASE. Authors were contacted for additional, unpublished data. RESULTS: Data on 61,281 individuals were included from 3 general population studies (Kalixanda study [Sweden], Loiano Monghidoro study [Italy], SILC study [China]) and 8 healthcheck studies (Japan, n 1; China, n 1; Taiwan, n 4; Korea, n 2). The prevalence of reflux esophagitis was 15.5% (Kalixanda), 11.8% (Loiano Monghidoro), and 6.4% (SILC); it ranged from 3.4% to 8.5% in health-check studies in Japan, China, and Korea (n 4), but was higher (mean, 15.6%; range, 9.0% 24.6%; n 4) in Taiwan. Hiatus hernia prevalence was 23.9% (Kalixanda), 43.0% (Loiano Monghidoro), and 0.7% (SILC), and 0.8% 19.5% in health-check studies (n 7). For endoscopically suspected esophageal metaplasia (ESEM), the prevalence was 10.3% (Kalixanda), 3.6% (Loiano Monghidoro), and 1.8% (SILC), and 0.0% 3.4% in health-check studies (n 4). The prevalence of reflux esophagitis among individuals without symptom-defined GERD was 12.1% (Kalixanda), 8.6% (Loiano Monghidoro), 6.1% (SILC), and 1.6% 22.8% (health-check studies; n 6). For individuals without symptom-defined GERD, the prevalence of ESEM was 9.4% (Kalixanda), 2.8% (Loiano Monghidoro), and 1.8% (SILC). CONCLUSIONS: The prevalence of reflux esophagitis is higher in Sweden and Italy than in China, Korea, and Japan, but is within the range reported in Taiwan. Hiatus hernia and ESEM are generally more prevalent in Europe than in Asia. A considerable proportion of individuals without symptom-defined GERD has reflux esophagitis or ESEM. Keywords: Endoscopy; Gastroesophageal Reflux Disease; General Population; Symptoms. Large-scale epidemiologic studies of gastroesophageal reflux disease (GERD) rely primarily on recognition of heartburn and regurgitation, the most prevalent and typical symptoms of GERD. Survey instruts must first recognize these symptoms as effectively as possible and, secondly, assess their frequency and severity, in order to make a judgt on the presence or absence of GERD. Heartburn and regurgitation occur occasionally in probably more than half of the general population and, in the majority of individuals, the frequency and severity of these symptoms are insufficient to have a clinically significant effect and therefore should not be categorized as causing disease. The Montreal Workshop has provided the most considered recent definition for when heartburn and/or regurgitation become sufficiently troublesome to be defined as GERD. 1 The Workshop concluded that, for the purposes of epidemiological studies, either mild heartburn and/or regurgitation occurring at least 2 days per week or moderate/severe heartburn and/or regurgitation occurring at least 1 day per week should lead to a symptombased diagnosis of GERD. 1 Although a diagnosis based on reflux symptoms is the most important method for recognition of GERD in both clinical practice and epidemiologic research, it is far from perfect. About one-third of patients with GERD who have troublesome upper abdominal and/or retrosternal symptoms will not be diagnosed on the basis of symptom evaluation because, in these individuals, reflux induces relatively nonspecific or atypical symptoms that are difficult to differentiate with confidence from causes other than GERD. 2 Also, some individuals who have reflux esophagitis and/or Barrett s esophagus have only minimal symptoms attributable to GERD, or even none at all. 3,4 For this reason, prevalence estimates of GERD from epidemiologic studies based on reflux symptom surveys alone will underdiagnose true GERD. This underdiagnosis may be more than counterbalanced by symptom evaluation incorrectly diagnosing GERD as present in a significant proportion of individuals in whom symptoms are due to other causes. Currently there are no published estimates of the falsepositive for GERD rate for the symptom-based GERD diagnosis. Endoscopy can be used to identify some of the individuals with reflux disease who will not be detected by reflux symptom evaluation. Furthermore, endoscopy is the only way that Bar- Abbreviations used in this paper: CI, confidence interval; ESEM, endoscopically suspected esophageal metaplasia; GERD, gastroesophageal reflux disease; LA, Los Angeles; OR, odds ratio; SILC, Systematic Investigation of Gastrointestinal Diseases in China by the AGA Institute /$

2 864 DENT ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 8 rett s esophagus can be diagnosed and reflux esophagitis recognized and graded for severity. Endoscopic surveys have also provided data on the prevalence of hiatus hernia, which is clearly implicated as a significant pathogenic factor for reflux disease and Barrett s esophagus. 5 Use of endoscopy alone in epidemiologic studies of GERD does, however, have substantial limitations, the main limitation being that esophageal mucosal breaks indicative of reflux esophagitis and/or Barrett s esophagus are present in fewer than half of individuals with GERD. 6 8 The limitations of the reflux symptom-based and endoscopic diagnoses of GERD mean that the information provided by these 2 methods is completary, both for routine clinical practice and epidemiologic research. The invasiveness and cost of endoscopy severely limits its use for large-scale populationbased epidemiologic studies. Despite this, relatively large-scale endoscopic studies have been carried out in recent years, some of which have made correlations with well-structured reflux symptom evaluations. The aim of this systematic review was to assess endoscopic findings and their relationship with reflux symptoms in the general population. This is the first systematic review of data arising from endoscopic population-based epidemiologic surveys. These studies are especially important for improving the docutation of geographic variations in the prevalence of GERD. Methods Literature Searches Systematic literature searches were conducted in PubMed and EMBASE on 30 October 2010, to identify population-based endoscopy studies reporting prevalence data for reflux esophagitis or Barrett s esophagus (Figure 1). Although data were extracted on the prevalence of hiatal hernia and Helicobacter pylori infection, these were not among the search terms used. Esophageal erosions or ulceration (mucosal breaks) were required to be present for the diagnosis of reflux esophagitis. Studies that diagnosed esophageal mucosal minimal changes such as erythema, edema, or friability as esophagitis were excluded, because evaluations of these criteria have not found them to be valid. 9 The following search strings were used to identify general population studies involving endoscopy: (endoscopy OR endoscopic OR endoscopically OR gastroduodenoscopy OR oesophagogastroduodenoscopy OR esophagogastroduodenoscopy) AND (general population OR population-based OR community OR survey OR epidemiology OR epidemiological OR epidemiologic OR cross-sectional). The search strings were combined with (esophagitis OR oesophagitis OR Barrett s esophagus OR Barrett s oesophagus) for PubMed searches, and with (esophagitis OR oesophagitis OR (Barrett AND (esophagus OR esophagus))) for EMBASE searches. To identify additional studies reporting data from routine health checks, offered on a large scale to the general population, the following search strings were used: (health check* OR medical check* OR physical check* OR routine check* OR physical examination*). These search strings were combined with (esophagitis OR oesophagitis OR Barrett s esophagus OR Barrett s oesophagus) for PubMed searches, and with (esophagitis OR oesophagitis OR (Barrett AND (esophagus OR oesophagus))) for EMBASE searches. Health checks, either employer-paid or self-paid, which routinely include endoscopy are offered on a large scale to the Figure 1. Flow chart of systematic literature searches.

3 August 2012 ENDOSCOPIC GENERAL POPULATION SURVEYS OF GERD 865 general population in Japan, Taiwan, mainland China, and Korea. Studies were excluded if they reported only autopsy data, if they provided data on esophageal inflammation without stating that the diagnosis was based solely on the presence or absence of mucosal breaks, if they were published as meeting abstracts only, or if they were not reported in the English language. The following data were extracted for surveys identified by the searches: sampling method, numbers enrolled, response rate, mean age and age range of participants, prevalence of H pylori infection, number of and whether they were blinded to symptoms, classification and prevalence of reflux esophagitis, criteria for and prevalence of hiatus hernia, and definition and prevalence of endoscopically suspected esophageal metaplasia (ESEM) and histologically confirmed esophageal columnar metaplasia. The prevalence of symptom-defined GERD was assessed using the Montreal Workshop criteria for epidemiologic studies, which state that either mild heartburn and/or regurgitation occurring at least 2 days per week or moderate/severe heartburn and/or regurgitation occurring at least 1 day per week should lead to a symptom-based diagnosis of GERD. 1 Studies identified in the searches were screened for technical validity of their endoscopic assessts. To be technically valid and so acceptable for inclusion in the primary analysis of this review, the main study data had to be derived prospectively from endoscopy, rather than from review of stored images. Authors of all studies that were accepted as technically valid were contacted by or post about additional, unpublished information. Sample size-weighted mean prevalence and sample size-weighted 95% confidence intervals (CIs) were calculated for reflux esophagitis data obtained from health-check studies. Results The searches identified 21 references relating to 16 studies that were potentially eligible for inclusion. Of these, 11 studies (conducted in a total of 61,281 individuals) were deemed technically valid for the purposes of this review. Three of the technically valid studies were formal epidemiologic surveys conducted in the general population (Table 1) and 8 were studies of individuals undergoing routine health checks (Suppletary Table 1). A total of 5 studies (all health-check studies) were judged technically invalid because the endoscopic assessts were carried out retrospectively using stored images; data from these studies are presented in the shaded sections in Suppletary Table 1, but are not included in the data values presented in the Results section or in the Figures. A flow chart of the systematic searches is shown in Figure 1. The most common reason for exclusion during the manual review was that the study was not population-based. One study from Taiwan (described in 2 reports 10,11 ) was excluded because it used a modified version of the Savary Miller classification that included erythema as a criterion for grade 1 reflux esophagitis. Another study, reporting health-check data from Korea, was excluded because it was not published in the English language. 12 Three publications from Taiwan described patient data from the same database, with the same start date but with different end dates, and thus with largely overlapping patient populations For these, only the publication with the most recent end date (ie, describing the largest number of patients) is presented here. 15 For all 8 technically valid, routine, health-check studies, the authors were contacted for additional, unpublished primary data. Replies were received from authors of 4 of these studies: from Y.-C. Lee for Tseng et al, 15 from C.-S. Hung for Hung et al, 16 from T.-S. Chen for Chen and Chang, 17 and from N. Kim for Kim et al. 18 The responses provided relevant, unpublished, suppletary data for inclusion in this systematic review. Additional, previously unpublished, relevant data were also obtained from the authors of all 3 general population studies included in this review. General Population Endoscopy Studies The 3 general population endoscopy studies eligible for inclusion were the Kalixanda study, conducted in Sweden, 3,4 the Loiano Monghidoro study, conducted in Italy, 19 and the Systematic Investigation of Gastrointestinal Diseases in China (SILC) study. 20 The main methods and outcomes are summarized in Table 1. Prevalence of endoscopic findings. Prevalence data for reflux esophagitis, hiatus hernia, and Barrett s esophagus are provided in Table 1, and in Figures 2 and 3. Each of these findings was substantially more prevalent in Sweden and Italy than in China. Most cases of reflux esophagitis were mild; similarly, for ESEM, the majority of cases had an extent of either less than 2 cm (Kalixanda and Loiano Monghidoro) or less than 3 cm (SILC) (Table 1). Prevalence of endoscopic findings according to frequency and severity of heartburn and regurgitation. The prevalence of reflux esophagitis was assessed in 4 and 3 different reflux symptom frequency groups in the Kalixanda and Loiano Monghidoro studies, respectively. In both studies, the prevalence of reflux esophagitis increased with increasing reflux symptom frequency (Figure 4). The prevalence of reflux esophagitis in individuals with and without symptomdefined GERD (according to the Montreal definition 1 ) was 29.0% and 12.1%, respectively, in the Kalixanda study (L. Agréus and J. Ronkainen, personal communication, 2011), 19.9% and 8.6%, respectively, in the Loiano Monghidoro study (F. Bazzoli and R.M. Zagari, personal communication, 2011), and 12.5% and 6.1%, respectively, in the SILC study. Overall, 62.6% (Kalixanda), 52.5% (Loiano Monghidoro), and 90.9% (SILC) of individuals with reflux esophagitis did not have symptom-defined GERD. The prevalence of hiatus hernia in individuals with and without symptom-defined GERD was 38.5% and 19.9%, respectively, in the Kalixanda study, % and 39.4%, respectively, in the Loiano Monghidoro study, 19 and 4.2% and 0.5%, respectively, in the SILC study. 20 Overall, 66.5% (Kalixanda), 69.8% (Loiano Monghidoro), and 71.4% (SILC) of individuals with hiatus hernia did not have symptom-defined GERD. The prevalence of ESEM in individuals with and without symptom-defined GERD (according to the Montreal definition 1 ) was 14.0% and 9.4%, respectively, in the Kalixanda study (L. Agréus and J. Ronkainen, personal communication, 2011), 5.5% and 2.8%, respectively, in the Loiano Monghidoro study (F. Bazzoli and R.M. Zagari, personal communication, 2011), and 1.8% and 2.1%, respectively, in the SILC study. 20 Of individuals with ESEM, 72.8% (Kalixanda), 59.4% (Loiano Monghidoro), and 94.7% (SILC) did not have symptom-defined GERD.

4 Table 1. Prevalence of Helicobacter pylori Infection, Reflux Esophagitis, Hiatus Hernia, and Barrett s Esophagus in General Population Studies (n 3) Study name (country, study period), reference Kalixanda (Sweden, ), Ronkainen et al, ,4 Loiano Monghidoro (Italy, ), Zagari et al, SILC (China, ), Zou et al, Sampling method and target population Questionnaire posted to every seventh adult from the national population register of Kalix and Haparanda Inhabitants of Loiano and Monghidoro identified from electoral roll as part of a first study (conducted ) Shanghai inhabitants selected randomly Participants N 1000 (response rate to questionnaire, 73.3%, of whom 47.1% underwent endoscopy); mean age, 54 y (range, y); 49% N 1033 (response rate, 67.4%); mean age, 58 y (range, y b ); 51% N 1029 (response rate, 32.7%); mean age, 50 y (range, 18 80y); 42% H pylori infection prevalence Endoscopists 339 (33.9%) N 3, with prior training, blinded to symptoms 596 (57.7%) N 3, with prior training, blinded to symptoms 738 (71.7%) N 3 e, with prior training, blinded to symptoms Reflux esophagitis Hiatus hernia Barrett s esophagus Classification Prevalence Criteria Prevalence Definition Prevalence LA Total, 155 (15.5%); grade A, 109; grade B, 39; grade C, 3; grade D, 2 Modified S-M c Total, 122 (11.8%); grades I/II d, 117; grades III/IV d,5 LA Total, 66 (6.4%); grade A, 42; grade B, 22; grade C, 2; grade D, 0 Gastric folds above the diaphragmatic pinch, after suction of excess air a Gastroesophageal junction extends (folds) at least 2 cm above the diaphragm Gastric folds extending at least 2 cm above hiatus 23.9% ESEM and ITECM (presence of goblet cells); 2 biopsy specis from short segts; 1 biopsy speci in every quadrant at 2 cm intervals in longer segts a 43.0% ESEM and ITECM; pairs of biopsy specis taken at 2 cm intervals from areas of suspected EM 0.7% ESEM by Prague C&M criteria Total ESEM, 103 (10.3%); 2 cm, 91; 2 cm, 12; ITECM, 16 (1.6%) Total ESEM, 37 (3.6%); 2 cm, 31; 2 cm, 6; ITECM, 13 (1.3%) ESEM, 19 (1.8%). C value e : 1 cm, 9; 1 to 2 cm, 2; 2 to 3 cm, 7; 3 cm, 1. M value e : 1 cm,0;1to 2 cm,6;2to 3 cm,8; 3 cm, 5 ECM, histologically confirmed esophageal columnar metaplasia; ITECM, intestinal-type esophageal columnar metaplasia; NR, not reported; S M, Savary Miller classification of reflux esophagitis. a L. Agréus and J. Ronkainen, personal communication, b F. Bazzoli and R.M. Zagari, personal communication, c Grade I, single or multiple nonconfluent erosions; grade II, confluent noncircumferential multiple erosions; grade III, circumferential erosions; grade IV, ulcer and/or stricture. d Grades not reported separately. e X. Ma, personal communication, DENT ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 8

5 August 2012 ENDOSCOPIC GENERAL POPULATION SURVEYS OF GERD 867 Figure 2. Prevalence of hiatus hernia in the 3 general population studies and in the 7 technically valid health-check studies that report these data. a Endoscopic criteria for hiatus hernia not stated. b Hiatus hernia defined as minimum 2 cm extent of stomach above diaphragmatic pinch. The prevalence of histologically confirmed, intestinal type, esophageal columnar metaplasia in individuals with and without symptom-defined GERD was 2.5% and 1.4%, respectively, in the Kalixanda study (L. Agréus and J. Ronkainen, personal communication, 2011), and 2.4% and 0.8%, respectively, in the Loiano Monghidoro study (F. Bazzoli and R.M. Zagari, personal communication, 2011). The presence of intestinal-type esophageal columnar metaplasia was not evaluated in the SILC study. Overall, 68.8% (Kalixanda) and 46.2% (Loiano Monghidoro) of individuals with histologically confirmed intestinal-type esophageal columnar metaplasia did not have symptom-defined GERD. Statistical associations between different endoscopic findings and symptoms. On univariate analyses in the Kalixanda study, reflux esophagitis (odds ratio [OR], 8.3; 95% CI, ) and hiatus hernia (OR, 13.0; 95% CI, ) were statistically significant risk factors for histologically confirmed, intestinal type, esophageal columnar metaplasia longer than 2 cm. 4 Multiple logistic regression analyses showed hiatus hernia to be a significant risk factor for reflux esophagitis (OR in individuals with 3 monthly reflux symptoms, 8.9; 95% CI, ; in individuals with 3 monthly reflux symptoms or no symptoms, 14.1; 95% CI, ). 3 Similar analyses showed that, in individuals with symptom-defined GERD, the relative risk of reflux esophagitis was 3.3 (95% CI, ) and that of hiatus hernia was 2.6 (95% CI, ). 3 There was no significant association of symptom-defined GERD with ESEM or histologically confirmed intestinal-type esophageal columnar metaplasia. 4 In the Loiano Monghidoro study, multivariate analyses showed reflux esophagitis to be associated with hiatus hernia (risk ratio, 3.3; 95% CI, ). 19 In individuals with symptomdefined GERD, the relative risk of reflux esophagitis was 2.6 (95% CI, ) and that of hiatus hernia was 1.6 (95% CI, ). In the SILC study, the prevalence of reflux esophagitis (12.5% vs 6.1%) and hiatus hernia (4.2% vs 0.5%) was higher in patients with symptom-defined GERD than in those without; hiatus hernia was present in 6.1% of individuals with reflux esophagitis, compared with 0.3% in those without. However, the low numbers associated with these findings precluded multivariate tests of association. 20 Endoscopic studies in individuals undergoing routine health checks. The 8 technically valid endoscopic studies were conducted prospectively in individuals undergoing routine health checks as part of large-scale programs (Suppletary Table 1, unshaded sections). Of these, 1 was from Japan, 4 from Taiwan, 1 from mainland China, and 2 from Korea. All 8 studies provided prevalence data for reflux esophagitis, 7 reported on the prevalence of hiatus hernia, and 5 on that of ESEM. Prevalence of endoscopic findings. The prevalence of reflux esophagitis ranged from 4.3% in mainland China

6 868 DENT ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 8 Figure 3. Prevalence of Barrett s esophagus in the 3 general population studies and in the 4 technically valid health-check studies that report these data. a Data not reported separately by extent. (1 study) to 15.6% in Taiwan (mean of 4 studies; 95% CI, 13.4% 17.8%; range, 9.0% 24.6%). For hiatus hernia, prevalence estimates ranged from 0.8% to 19.5%, with only 2 of the health-check studies finding a prevalence of hiatus hernia in excess of 7.5% (Figure 2). Only 4 studies stated the diagnostic criteria used and in each of these, the threshold for the presence of hiatus hernia was when the diaphragmatic hiatus was judged to be at least 2 cm below either the squamocolumnar junction or the start of the tubular esophagus. The reported prevalence of ESEM ranged from 0% and 0.3% (Taiwan; 2 studies) to 3.4% (Korea; 1 study). Of the 4 valid health-check studies that reported on the prevalence of ESEM, 2 did not report using specific endoscopic landmarks for locating the gastroesophageal junction 15,17 (and Y.C. Lee, personal communication, 2011), 1 used the tops of the gastric mucosal folds, 21 and 1 described use of 3 different landmarks 18 (if discrepancies occurred, these were resolved by using the tops of the gastric mucosal folds as landmarks; N. Kim, personal communication, 2011). Histologic data were reported only for intestinal-type and gastric-type esophageal columnar metaplasia combined, and the prevalence of any type of metaplasia was 0.06% and 0.4% in Taiwan (2 studies), and 1.1% in Korea (1 study). However, unpublished data from the study in Taiwan by Tseng et al 15 show that, of the 12 individuals with any type of metaplasia, in 9 intestinal-type esophageal columnar metaplasia was found and in 3 only gastric-type esophageal columnar metaplasia was demonstrated (Y.C. Lee, personal communication, 2011). Prevalence of endoscopic findings according to frequency and severity of heartburn and regurgitation. Six of the 8 technically valid health-check studies reported the prevalence of reflux esophagitis in individuals with and without heartburn and regurgitation of varying severity, or provided data that made it possible to calculate these prevalence estimates (Figure 5). The frequency threshold used to report heartburn and regurgitation varied considerably, ranging from the presence of symptoms on 3 or more days per week, 14 to 1 symptom episode in 6 months 18,22,23 ; 1 study did not report a symptom frequency threshold. In all 6 studies, the prevalence of reflux esophagitis was higher in individuals with heartburn and regurgitation (range, 14.2% 45.0%) than in those without these symptoms (range, 1.6% 22.9%); in the 3 studies that reported P values, the differences were found to be statistically significant (Figure 5). The proportion of individuals with reflux esophagitis who had only infrequent reflux symptoms ranged from 33.6% to 90.9%. None of the health-check studies reported on the prevalence of hiatus hernia in individuals with and without reflux symptoms. The Chinese health-check study, conducted by Peng et al, reported on the prevalence of ESEM in individuals without and with heartburn and regurgitation in the previous year, and

7 August 2012 ENDOSCOPIC GENERAL POPULATION SURVEYS OF GERD 869 Figure 4. Prevalence of reflux esophagitis in the different reflux symptom subgroups assessed in the 3 general population studies. Symptom subgroups within each study are mutually exclusive. Symptom-defined GERD categorized by mild GERD symptoms on 2 or more days per week, or moderate/severe GERD symptoms on 1 or more days per week. found this to be 0.5% (11/2270) and 5.2% (16/310), respectively (P.0001). 21 The reporting by Park et al of a prevalence of any type of metaplasia of 0.7% (77/10,578) and 1.0% (116/11,254) in participants without and with reflux symptoms in the previous year, is confounded by their exclusion of individuals with reflux esophagitis from this analysis. 22 Statistical associations between endoscopic findings and symptoms. Seven studies reported data on the relationship between hiatus hernia and reflux esophagitis; all but 1 15 found a significant association. In the 4 studies that reported ORs for this association, these were 3.5 (95% CI, ), (95% CI, ), (95% CI, ), 21 and 5.4 ( ) 18 ; all used multivariate analyses. In the 3 studies that reported prevalence data for hiatus hernia in individuals with vs without reflux esophagitis, these were 13.8% vs 3.8%, % vs 2.4%, 17 and 68.6% vs 9.2% 26 (all P.05). Two studies reported data on the relationship between hiatus hernia and Barrett s esophagus. One reported on the prevalence of hiatus hernia in individuals with and without ESEM, and found this to be significantly different (7.1% vs 0.8%; P.001). 15 The other study found hiatus hernia to be a risk factor for esophageal columnar metaplasia on multivariate analysis (OR, 5.01; 95% CI, ). 27 One study reported on the associations of ESEM with reflux esophagitis (OR, 8.3; 95% CI, ) and hiatus hernia (OR, 3.6; 95% CI, ), and found these to be statistically significant using multivariate analyses. 21 Three studies reported data on the relationship between reflux symptoms and endoscopic findings. Only 1 of these assessed the relationship between symptom-defined GERD and endoscopic findings. 25 The authors found that reflux esophagitis was significantly more prevalent in individuals with than without symptom-defined GERD (45.0% vs 14.9%; P.05). Of the other 2 studies, 1 observed associations of reflux esophagitis (OR, 16.3; 95% CI, ) and ESEM (OR, 9.0; 95% CI, ) with reflux symptoms using multivariate analyses, 21 and the other observed a higher prevalence of reflux symptoms in individuals with than without reflux esophagitis (38.1% vs 6.7%; P.005), 26 although frequency thresholds for reflux symptoms were low ( 6 monthly) 21 or not defined. 26 Discussion This systematic review identified 11 technically valid endoscopic studies that evaluated the prevalence of reflux esophagitis in a total of 61,281 individuals. Of these, 10 studies also assessed the prevalence of hiatus hernia and 7 studies recorded the prevalence of Barrett s esophagus. The prevalence of reflux esophagitis was substantially higher in Sweden and Italy than in China, Korea, and Japan, but was within the range reported in Taiwan. Hiatus hernia and ESEM were generally more prevalent in Europe than in Asia. The prevalence of histologically confirmed, intestinal-type, esophageal columnar metaplasia was also higher in Europe than in the 1 study from Asia in which such data were recorded 15 (Y.C. Lee, personal communication, 2011). A large proportion of the individuals who had reflux esophagitis (33.6% 90.9%), ESEM (59.4% 94.7%), hiatus hernia (66.5% 71.4%), and histologically confirmed esophageal columnar metaplasia (46.2% 68.8%) did not have symptom-defined GERD. Conversely, a considerable proportion of individuals without symptom-defined GERD had reflux esophagitis (2.3% 22.9%), hiatus hernia (2.1% 39.4%), ESEM (0.5% 9.4%), or intestinal-type esophageal columnar metaplasia (0.8% 1.4%). Overall Evaluation of the Quality of the Data The 3 structured endoscopic population surveys that met inclusion criteria for this review each report endoscopic findings in groups of 1000 to 1033 individuals. The groups that underwent endoscopy appear to be reasonably representative of the adult general population, with a few relatively minor caveats. Although the Loiano Monghidoro study did not include adults aged younger than 32 years, overall the mean age and age

8 870 DENT ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 8 Figure 5. Prevalence of reflux esophagitis in different reflux symptom groups in the 7 technically valid health-check studies that reported these values or provided data for these to be calculated. For the study by Tseng et al, 15 data from the subpopulation described in the paper by Lee et al, 2006 were used, 14 as equivalent symptom data were not reported (NR) in the main publication. range did not differ greatly between the Loiano Monghidoro study, and the Kalixanda and SILC studies. In all 3 population surveys, were blinded as to the presence and pattern of gastrointestinal symptoms, thus removing 1 potential source of observer bias. 9 Potential for inaccurate endoscopic assesst was further minimized in these studies by using very few working in a single institution. These were calibrated before the study start by formal training and standardization of the diagnostic/grading criteria used. The major strength of the included, technically valid, healthcheck endoscopic studies is the large number of individuals evaluated. Health checks, either employer or self-paid, which routinely include endoscopy are offered on a large-scale to the general population in Japan, Taiwan, mainland China, and Korea. The mean age of participants (when reported) was mostly lower than in the Kalixanda, Loiano Monghidoro, and SILC studies, with the age ranges being broadly comparable among the studies, thus refuting the assumption that access to health-check endoscopy is guided by age criteria. Some selection bias is likely to have been introduced in the health-check studies because of the way that these are usually accessed. In by far the largest health-check study (n 19,812), from Taiwan, 15 H pylori infection was screened for and frequently treated well before the endoscopy (Y.C. Lee, personal communication, 2011). Consequently, with regard to H pylori infection, this population should not be regarded as representative of the Taiwanese population. In most of the health-check endoscopic studies, were blinded to the presence and pattern of gastrointestinal symptoms. However, it is likely that the esophageal endoscopic assessts were more prone to observer error than in the Kalixanda, Loiano Monghidoro, and SILC studies because of the usual involvet of a relatively large number of institutions and, and limited attempts to formally calibrate the interpretation of endoscopic findings. Prevalence and Severity of Reflux Esophagitis The widespread adoption of the Los Angeles (LA) classification of reflux esophagitis is reflected by its use in 2 of the 3 epidemiologic surveys and in 7 of the 8 technically valid health-check studies. This methodological standardization supports the validity of comparisons among studies. The versions of the Savary Miller classification used in 2 of the studies and the LA classification require presence of mucosal breaks and exclude minimal change as diagnostic criteria for reflux esophagitis. The Kalixanda and Loiano Monghidoro studies provide the only available large-scale population survey data on reflux esophagitis in Caucasian populations. Notably, there are no comparable data from the United States, where population-based symptom surveys suggest that reflux disease is about 2 times more prevalent than in Scandinavia and Western Europe. 28 The prevalence of reflux esophagitis in the SILC study (6.4%) was found to be about half that reported

9 August 2012 ENDOSCOPIC GENERAL POPULATION SURVEYS OF GERD 871 in the Kalixanda and Loiano Monghidoro studies (15.5% and 11.8%, respectively). The prevalence of reflux esophagitis in technically valid health-check endoscopy studies in Japan, China, and Korea ranged from 3.4% to 8.5%, consistent with the conclusions drawn in the SILC study that reflux esophagitis was less prevalent in these countries than in Sweden and Italy. However, prevalence estimates varied widely from 9.0% to 24.6% in Taiwan. The reasons for this are unclear. H pylori infection rates have been shown to be negatively associated with reflux esophagitis. 29 H pylori infection rates were reported in only 1 of the 4 valid studies from Taiwan, in which it was 68.3% (the prevalence of reflux esophagitis in that study was 12.0%). 17 Prevalence of Hiatus Hernia Most of the studies that reported the prevalence of hiatus hernia found that this was a significant risk factor for reflux esophagitis. 3,17 19,21,24 26 This finding is consistent with a growing literature that demonstrates that the mechanical effects of hiatus hernia, and its associated diaphragmatic crural laxity, predispose to relatively large-volume reflux of liquid gastric content during transient lower esophageal relaxations. 5 Accordingly, it seems likely that the lower prevalence of hiatus hernia in the Asian populations studied is an important factor underlying the low prevalence of reflux disease relative to countries with predominantly Caucasian populations. Recently, the collagen-type III 1 gene was found to be a risk factor for reflux disease and hiatus hernia in. 30 Study of the frequency of this gene in general populations could possibly shed additional light on factors that could contribute to regional variations in the prevalence of reflux disease. The reliability of the data on hiatus hernia is almost certainly less than those for reflux esophagitis, because varying endoscopic diagnostic criteria were used. This reflects the lack of widely accepted uniform criteria. Unvalidated criteria for endoscopic detection and classification of even relatively minor degrees of hiatal laxity and displacet of the gastroesophageal junction above the diaphragmatic crura do exist, 31 but these were not applied in any of the studies included in this review. There is a need for further developt, testing, and widespread adoption of validated criteria for detection and grading of hiatus hernia and hiatal laxity. Prevalence of Barrett s Esophagus Comtaries about variations in the prevalence of Barrett s esophagus in different populations have usually failed to recognize that quite widely differing diagnostic criteria have been used in the published studies, which reflects the different definitions in current use. Even if only histologic criteria are applied, there are major differences in these criteria used for diagnosis of Barrett s esophagus among the studies included in this review. The 2 European studies reported on the prevalence of histologically confirmed, intestinal-type, esophageal metaplasia, whereas the Asian studies published only the combined prevalence of gastric- and intestinal-type metaplasia; thus, these data cannot be compared directly. However, use of ESEM as the finding that defines the presence of Barrett s esophagus confirms the strong circumstantial evidence that Barrett s esophagus is much more prevalent in a country such as Sweden, when compared with China that is, the Swedish prevalence is more than 5 times that of China when comparable criteria are used. The different prevalence of hiatus hernia and H pylori infection in China compared with Italy and Sweden are plausible factors that could contribute to the variations in the prevalence of ESEM found in the 3 structured epidemiologic surveys. There is strong evidence that ESEM is superior to demonstration of intestinal-type metaplasia as a diagnostic criterion for Barrett s esophagus, which led the Montreal Workshop on reflux disease to advocate abandont of the restrictive intestinal-type esophageal columnar metaplasia definition of Barrett s esophagus in Since then, the evidence has become even more convincing in support of this recomdation. 32 The reasons for this are, first, that it is now clear that the risk of esophageal adenocarcinoma is substantial in all types of esophageal columnar metaplasia. Second, even if intestinal-type metaplasia were uniquely premalignant, its accurate detection requires very extensive biopsy sampling of the metaplasia, with the best detection rates of intestinal-type metaplasia requiring 8 16 biopsies. 32 Such intense histologic sampling of ESEM is rarely, if ever, carried out in clinical practice and is difficult to resource and justify ethically for an epidemiologic survey. Consequently, none of the studies included in this review used such an intensive biopsy protocol. The endoscopic recognition of esophageal columnar metaplasia poses challenges and potential inaccuracies of its own. The key judgt needed for reliable diagnosis is the accurate endoscopic location of the gastroesophageal junction, because any columnar-appearing mucosa above this level must be considered metaplastic. Consequently, the developt of the Prague C & M criteria included evaluation of the best endoscopic landmarks for the gastroesophageal junction. 33 It was concluded that the tops of the gastric mucosal folds, observed (importantly) during only mild air distension of the stomach and esophagus, was the best landmark for the gastroesophageal junction. The SILC, Kalixanda, and Loiano Monghidoro studies all used the tops of the gastric mucosal folds as the landmark for the gastroesophageal junction 4 (and F. Bazzoli and R.M. Zagari, personal communication, 2011). Concluding Remarks To our knowledge, this is the first systematic review of data arising from large-scale endoscopic surveys that are informative about the general population. The main strengths of this review are that it includes data from a large number of individuals and different geographic regions. Furthermore, additional, unpublished data relevant to this review were obtained for all 3 general population studies and for 4 of the 8 technically valid health-check studies. Limitations inherent in the source data include uncertainty about how representative the individuals from the health-check endoscopic studies were of the general population and comparability between studies, especially with regard to different endoscopic methodologies and diagnostic criteria used. In conclusion, data from general population and healthcheck endoscopic surveys show a substantially higher prevalence of reflux esophagitis in Sweden and Italy than in China, Korea, and Japan, although the prevalence in Taiwan was within the range reported in the European studies. Use of ESEM as the finding that defines the presence of Barrett s esophagus confirms the strong circumstantial evidence that Barrett s esopha-

10 872 DENT ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 8 gus is generally more prevalent in Europe than in Asia. H pylori infection rates and the differences in the prevalence of hiatus hernia are consistent with an influence of these variables on reflux esophagitis and ESEM prevalence. The authority of future endoscopic surveys will benefit from careful standardization of endoscopic diagnostic and grading criteria within and across studies. Formal training of contributing in the use of such criteria is important. From an epidemiologic and pathophysiological perspective, there is a pressing need for developt of practical and well-researched criteria for the endoscopic recognition and grading of hiatus hernia and hiatal laxity. Suppletary Material Note: To access the suppletary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at and at doi: / j.cgh References 1. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101: Dent J, Vakil N, Jones R, et al. Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatt: the Diamond study. Gut 2010;59: Ronkainen J, Aro P, Storskrubb T, et al. High prevalence of gastroesophageal reflux symptoms and esophagitis with or without symptoms in the general adult Swedish population: a Kalixanda study report. Scand J Gastroenterol 2005;40: Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barrett s esophagus in the general population: an endoscopic study. Gastroenterology 2005;129: Dent J. Pathogenesis of gastro-oesophageal reflux disease and novel options for its therapy. Neurogastroenterol Motil 2008; 20(Suppl 1): Thomson AB, Barkun AN, Armstrong D, et al. The prevalence of clinically significant endoscopic findings in primary care patients with uninvestigated dyspepsia: the Canadian Adult Dyspepsia Empiric Treatt - Prompt Endoscopy (CADET-PE) study. Alit Pharmacol Ther 2003;17: Veldhuyzen van Zanten SJ, Thomson AB, Barkun AN, et al. The prevalence of Barrett s oesophagus in a cohort of 1040 Canadian primary care patients with uninvestigated dyspepsia undergoing prompt endoscopy. Alit Pharmacol Ther 2006;23: Kulig M, Nocon M, Vieth M, et al. Risk factors of gastroesophageal reflux disease: methodology and first epidemiological results of the ProGERD study. J Clin Epidemiol 2004;57: Bytzer P, Havelund T, Hansen JM. Interobserver variation in the endoscopic diagnosis of reflux esophagitis. Scand J Gastroenterol 1993;28: Chang CS, Poon SK, Lien HC, et al. The incidence of reflux esophagitis among the Chinese. Am J Gastroenterol 1997;92: Lien HC, Chang CS, Yeh HZ, et al. Increasing prevalence of erosive esophagitis among Taiwanese aged 40 years and above: a comparison between two time periods. J Clin Gastroenterol 2009;43: Yoo SS, Lee WH, Ha J, et al. [The prevalence of esophageal disorders in the subjects examined for health screening]. Korean J Gastroenterol 2007;50: [in Korean]. 13. Chen MJ, Wu MS, Lin JT, et al. Gastroesophageal reflux disease and sleep quality in a Chinese population. J Formos Med Assoc 2009;108: Lee YC, Wang HP, Chiu HM, et al. Comparative analysis between psychological and endoscopic profiles in patients with gastroesophageal reflux disease: a prospective study based on screening endoscopy. J Gastroenterol Hepatol 2006;21: Tseng PH, Lee YC, Chiu HM, et al. Prevalence and clinical characteristics of Barrett s esophagus in a Chinese general population. J Clin Gastroenterol 2008;42: Hung CS, Lee CL, Yang JN, et al. Clinical application of Carlsson s questionnaire to predict erosive GERD among healthy Chinese. J Gastroenterol Hepatol 2005;20: Chen TS, Chang FY. The prevalence and risk factors of reflux esophagitis among adult Chinese population in Taiwan. J Clin Gastroenterol 2007;41: Kim N, Lee SW, Cho SI, et al. The prevalence of and risk factors for erosive oesophagitis and non-erosive reflux disease: a nationwide multicentre prospective study in Korea. Alit Pharmacol Ther 2008;27: Zagari RM, Fuccio L, Wallander MA, et al. Gastro-oesophageal reflux symptoms, oesophagitis and Barrett s oesophagus in the general population: the Loiano-Monghidoro study. Gut 2008;57: Zou D, He J, Ma X, et al. Epidemiology of symptom-defined gastroesophageal reflux disease and reflux esophagitis: the systematic investigation of gastrointestinal diseases in China (SILC). Scand J Gastroenterol 2011;46: Peng S, Cui Y, Xiao YL, et al. Prevalence of erosive esophagitis and Barrett s esophagus in the adult Chinese population. Endoscopy 2009;41: Park JJ, Kim JW, Kim HJ, et al. The prevalence of and risk factors for Barrett s esophagus in a Korean population: a nationwide multicenter prospective study. J Clin Gastroenterol 2009;43: Shim KN, Hong SJ, Sung JK, et al. Clinical spectrum of reflux esophagitis among 25,536 Koreans who underwent a health check-up: a nationwide multicenter prospective, endoscopybased study. J Clin Gastroenterol 2009;43: Yasuhara H, Miyake Y, Toyokawa T, et al. Large waist circumference is a risk factor for reflux esophagitis in Japanese males. Digestion 2010;81: Lin BR, Wong JM, Yang JC, et al. Limited value of typical gastroesophageal reflux disease symptoms to screen for erosive esophagitis in Taiwanese. J Formos Med Assoc 2003;102: Lee SJ, Song CW, Jeen YT, et al. Prevalence of endoscopic reflux esophagitis among Koreans. J Gastroenterol Hepatol 2001;16: Park JJ, Kim JW, Kim HJ, et al. The prevalence of and risk factors for Barrett s esophagus in a Korean population: a nationwide multicenter prospective study. J Clin Gastroenterol 2009;43: Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastrooesophageal reflux disease: a systematic review. Gut 2005;54: Raghunath A, Hungin AP, Wooff D, et al. Prevalence of Helicobacter pylori in patients with gastro-oesophageal reflux disease: systematic review. BMJ 2003;326: Asling B, Jirholt J, Hammond P, et al. Collagen type III alpha I is a gastro-oesophageal reflux disease susceptibility gene and a male risk factor for hiatus hernia. Gut 2009;58: Kim GH, Song GA, Kim TO, et al. Endoscopic grading of gastroesophageal flap valve and atrophic gastritis is helpful to predict gastroesophageal reflux. J Gastroenterol Hepatol 2008;23: Dent J. Barrett s esophagus: a historical perspective, an update on core practicalities and predictions on future evolutions

11 August 2012 ENDOSCOPIC GENERAL POPULATION SURVEYS OF GERD 873 of managet. J Gastroenterol Hepatol 2011;26(Suppl 1): Sharma P, Dent J, Armstrong D, et al. The developt and validation of an endoscopic grading system for Barrett s esophagus: the Prague C& M criteria. Gastroenterology 2006;131: Reprint requests Address requests for reprints to: John Dent, MD, Departt of Gastroenterology and Hepatology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. john.dent@ health.sa.gov.au; fax: Acknowledgts The authors thank Jukka Ronkainen, Pertti Aro, and Tom Storskrubb, of the Center for Family and Community Medicine, Departt of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden, for their contribution to the Kalixanda study and for providing relevant, unpublished, suppletary data for inclusion in this systematic review; Rocco Maurizio Zagari, from the Departt of Clinical Medicine, University of Bologna, Bologna, Italy, for his contribution to the Loiano Monghidoro study and for providing relevant, unpublished, suppletary data for inclusion in this systematic review; and Xiuiqang Ma, from the Departt of Health Statistics, Second Military Medical University, Shanghai, China, for his contribution to the SILC study and for providing relevant, unpublished, suppletary data for inclusion in this systematic review; and the following authors of health-check studies for providing relevant, unpublished, suppletary data for inclusion in this systematic review: Y.C. Lee, C.-S. Hung, T.-S. Chen, and N. Kim. Conflicts of interest The authors disclose no conflicts. Funding This study was funded by AstraZeneca R&D, Mölndal, Sweden.

12 Suppletary Table 1. Prevalence of Helicobacter pylori Infection, Reflux Esophagitis, Hiatus Hernia, and Barrett s Esophagus in Both Technically Valid and Invalid Routine Health-Check Studies (Valid, n 8; Invalid, n 5) Country Study period, reference Participants Endoscopic assesst Japan , Yasuhara et al, Japan NR, Yamagishi et al, Japan , Moki et al, Japan , Akiyama et al, Taiwan , Tseng et al, Taiwan , Hung et al, Taiwan 2002, Lin et al, Taiwan , Chen and Chang, Taiwan , Lai et al, Mainland China Korea , Peng et al, , Kim et al, 2008; Park et al, 2009; Shim et al, N 1495; median age, 50 y (range, y); 55% N 6307; mean age, 63 y (range, NR); 49% N 5159; mean age, 47 y (range, 20 to 80 y); 70% N 869; median age, 66 y (range, 29 91); 53% N 19,812; mean age, 52 y (range, 14 95); 55% N 778; mean age, 49 y (range, 22 83); 63% N 521; mean age, 51 y (range, 15 81); 60% N 482; mean age, 57 y (range, d ); 58% N 1622; mean age, 51 y (range, 14 88); 41% N 2580; mean age, 45 y (range, 18 75); 50% N 25,536; mean age, 47 y (range, g ); 60% examination by 4 Retrospective examination of filed digital endoscopic images by 2 Retrospective review of endoscopic findings (number of NR) Retrospective examination of filed digital endoscopic images by 2 examination by 9 b examination by 5 c examination by 1 endoscopist examination by 8 d Retrospective review (number of NR) examination by 2 examination by 51 who were trained at a workshop H pylori infection prevalence Reflux esophagitis Hiatus hernia Barrett s esophagus Classification Prevalence Criteria Prevalence Definition Prevalence NR LA Total, 127 (8.5%); grade A, 96; grade B, 27; grade C, 4; grade D, 0 NR LA Total, 410 (6.5%); grade A, 236; grade B, 150; grade C, 17; grade D, 7 NR LA Total, 191 (3.7%); grades NR NR LA Total, 165 (19.0%); grade A/B, a 152; grade C/D, a 13 NR LA Total, 3129 (15.8%); grade A, 2446; grade B, 502; grade C, 164; grade D, 17 NR LA Total, 70 (9.0%); grade A/ B, a 63; grade C/D, a 7 NR LA Total, 128 (24.6%); grade A, 94; grade B, 31; grade C, 2; grade D, e (68.3% e ) 346/654 (52.9%) 723 (28.0%) 13,005 (50.9%) LA Total, 58 (12.0%); grade A, 31; grade B, 20; grade C, 5; grade D, 2 Diaphragm and squamo-columnar junction separated by 2 cm 19.5% (28% in ; 9% in wo) NR NR ESEM (methodological details NR; graded as 1 cm; 1 3 cm; 3 cm) NR NR Valid Total, 684 (10.8%); 1 cm, 574; 1 3 cm, 89; 3 cm, 21 Technical validity of study Invalid NR NR NR NR Invalid Distance between the gastro-esophageal junction and diaphragmatic hiatus 2 cm Diaphragm and squamo-columnar junction separated by 2 cm Overall prevalence NR ESEM by Prague C&M criteria 0.8% ESEM and ECM ( 2 biopsies taken from endoscopically visible lesion) Total, 374 (43.0%); short, 370; long, 4 ESEM, 56 (0.3%); short, 49; long, 7; ECM, 12 (0.06%); ITECM, 9 b ; GTECM, 3 b NR NR ECM ( 4 biopsies) c ESEM, NR; ECM, 3 c (0.4% c ) Hernial sac 2 cm long LA Total, 344 a (21.2%) Presence of gastric wall above diaphragmatic hiatus LA LA Total, 110 (4.3%); grade A/B, a 100; grade C/D, a 10 Total, 2019 (7.9%); grade A, 1497; grade B, 471; grade C/D, a 51 Invalid Valid Valid 7.5% NR NR Valid NR 5.2% ESEM 0 (0.0%) Valid 3.2% NR NR Invalid Difficult to interpret f 1.8% ESEM Total, 27 (1.0%); short, 22; long, 5 NR 2.7% ESEM (reddish colored mucosa of columnar lined esophagus) and ECM (4-quadrant biopsy specis at 1 cm intervals) ESEM, 864 (3.4%); ECM, 215 (1.1% h ) Valid Valid Continued. August 2012 ENDOSCOPIC GENERAL POPULATION SURVEYS OF GERD 873.e1