In Barrett s esophagus (BE), the normal squamous epithelium

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1 GASTROENTEROLOGY 2005;129: CLINICAL ALIMENTARY TRACT Prevalence of Barrett s Esophagus in the General Population: An Endoscopic Study JUKKA RONKAINEN,*, PERTTI ARO,* TOM STORSKRUBB,*, SVEN ERIK JOHANSSON,* TORE LIND, ELISABETH BOLLING STERNEVALD,*, MICHAEL VIETH, MANFRED STOLTE, NICHOLAS J. TALLEY, #, ** and LARS AGRÉUS* *Centre for Family Medicine, Karolinska Institutet, Stockholm, Sweden; Primary Health Care Center, Keminmaa, Finland; Department of Medicine, Kalix Hospital, Kalix, Sweden; AstraZeneca R&D, Mölndal, Sweden; Institute of Pathology, Bayreuth, Germany; # Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota; and **Department of Medicine, University of Sydney, Sydney, Australia See editorial on page Background & Aims: Barrett s esophagus (BE) is associated with esophageal adenocarcinoma, the incidence of which has been increasing dramatically. The prevalence of BE in the general population is uncertain because upper endoscopy is required for diagnosis. This study aimed to determine the prevalence of BE and possible associated risk factors in an adult Swedish population. Methods: A random sample (n 3000) of the adult population (n 21,610) in 2 municipalities was surveyed using a validated gastrointestinal symptom questionnaire (response rate, 74%); a random subsample (n 1000; mean age, 53.5 years; 51% female) underwent upper endoscopy. Endoscopic signs suggestive of columnar-lined esophagus (CLE) were defined as mucosal tongues or an upward shift of the squamocolumnar junction. BE was diagnosed when specialized intestinal metaplasia was detected histologically in suspected CLE. Results: BE was present in 16 subjects (1.6%; 95% confidence interval, ): 5 with a long segment and 11 with a short segment. Overall, 40% reported reflux symptoms and 15.5% showed esophagitis; 103 (10%) had suspected CLE, and 12 (1.2%) had a visible segment >2 cm. The prevalence of BE in those with reflux symptoms was 2.3% and in those without reflux symptoms was 1.2% (P.18). In those with esophagitis, the prevalence was 2.6%; in those without, the prevalence was 1.4% (P.32). Alcohol (P.04) and smoking (P.047) were independent risk factors for BE. Conclusions: BE was found in 1.6% of the general Swedish population. Alcohol and smoking were significant risk factors. In Barrett s esophagus (BE), the normal squamous epithelium in the distal esophagus is replaced by histologically confirmed specialized intestinal metaplasia (SIM). 1 3 It is considered one of the most important complications of gastroesophageal reflux disease due to its association with adenocarcinoma. 4,5 Esophageal adenocarcinoma has been estimated to develop in about 0.5% 1.0% of patients with BE annually 6 9 and is now the most rapidly increasing cancer in the Western world Importantly, esophageal adenocarcinoma is often found without any history of reflux symptoms. 13 The figures on prevalence of BE vary considerably. 5 There may be several explanations for this discrepancy, such as the time point of assessment, patient selection, and endoscopic and histologic criteria. In an autopsy study in Olmsted County, Cameron et al 14 found a prevalence of as low as 0.4% in a forensic medicine population. In 1128 consecutive patients with reflux symptoms or dyspepsia referred for endoscopy in primary care, the prevalence was 1% in the whole population and 4.4% in the gastroesophageal reflux disease enriched population. 15 In a German outpatient study of 6215 patients with reflux symptoms, the overall prevalence was reported to be 4.9%; however, in those with esophagitis, 8.4% had BE. 16 A remarkably high prevalence of BE of 25% was reported among mainly male veterans Abbreviations used in this paper: BE, Barrett s esophagus; CI, confidence interval; CLE, columnar-lined esophagus; EGD, esophagogastroduodenoscopy; LSBE, long-segment Barrett s esophagus; OR, odds ratio; SIM, specialized intestinal metaplasia; SSBE, short-segment Barrett s esophagus by the American Gastroenterological Association /05/$30.00 doi: /j.gastro

2 1826 RONKAINEN ET AL GASTROENTEROLOGY Vol. 129, No. 6 without reflux symptoms attending a sigmoidoscopy screening program but who also underwent an upper gastrointestinal endoscopy. 17 Similarly, in a colonoscopy screening program, Rex et al found a prevalence of BE of 8.3%, with long segment in 2.6% of those with reflux symptoms, compared with 5.6% and 0.4%, respectively, of those without reflux symptoms. 18 Although these studies all evaluated selected populations, they have emphasized a presumptive huge public health problem. To target the problem adequately, data from an unbiased general population are required and have not been available to date. The aim of this study was to determine the prevalence of BE and associated risk factors in the adult general population, irrespective of reflux symptoms. Patients and Methods Setting The setting consisted of 2 neighboring communities in northern Sweden, Kalix and Haparanda, with 18,408 and 10,580 inhabitants, respectively (as of December 1998). The age and sex distribution was similar to the national average in Sweden. 19 This study was approved by the Umeå University Ethics Committee and conducted in accordance with the revised Declaration of Helsinki in Sampling By using the computerized national population register, covering all citizens in the 2 communities by date of birth order, a representative sample was generated. Every seventh adult (n 3000) from the target population (20 80 years of age, n 21,610 in September 1998) was drawn, a procedure equivalent to random sampling. The sampled subjects were then, by a computerized process, given an identification number (ID ) in random order. Study Design and Logistics The study population (n 3000) was contacted by mail and invited to take part; this invitation included a validated questionnaire, the Abdominal Symptom Questionnaire, 20,21 to be returned by mail. A total of 2860 subjects were available at the time for invitation. 19 We aimed to perform an esophagogastroduodenoscopy (EGD) in one third of the study population, that is, 1000 individuals who formed the EGD study sample (4.6% of the target population). The participants were invited to a visit in the clinic in identification number order, for logistic reasons during a 2.5-year period, starting with the lowest available identification number. At the EGD visit, the participants were asked about their consumption of aspirin, nonsteroidal anti-inflammatory drugs, antacids, H 2 -receptor antagonists, and proton pump inhibitors over the past 3 months and about their tobacco (smoking or snuff) and alcohol use. A venous blood sample for Helicobacter pylori serology was also taken. Details regarding study logistics, sampling procedure, and baseline demographics were reported previously. 19,22 Questionnaire and Response Rate The Abdominal Symptom Questionnaire used in this investigation has been validated and previously described in detail The cutoff for reporting symptoms was that the symptoms should have been at least troublesome at some time during the past 3 months. An extended Abdominal Symptom Questionnaire with added symptom frequency evaluation (daily, weekly, past 3 months) was completed by the EGD study sample (n 1000) immediately before the endoscopy. A total of 2122 individuals completed the postal questionnaire, which corresponds to a response rate of 74% after 2 postal reminders. These responders were representative of the local population. To complete the 1000 upper endoscopies, 1563 responders to the Abdominal Symptom Questionnaire were approached; 364 declined, 74 had moved or could not be reached, 124 had medical contraindications, and 1 refused biopsy. Thus, the response rate for those eligible for investigation was 73%. The EGD study sample (mean age, 53.5 years; 51% female) was significantly older than the study population (by a mean of 3.7 years; P.01), mainly due to a lower response rate among the symptom-free youngest one fourth of the study sample, but there was no statistically significant difference in sex distribution. In total, the sex and age distribution for the 1000 subjects who responded to the questionnaire at both assessments closely reflects the 2122 responders to the postal questionnaire and the Swedish population, as described in detail previously. 19 Hence, a representative cohort of 1000 subjects invited for an upper endoscopy was evaluated. Endoscopy The EGDs in the survey were provided by 2 endoscopists in primary care and 1 endoscopist in secondary care; the 2 endoscopy units cover the whole catchment area. Before endoscopy, the 3 endoscopists were blinded to the medical history and symptoms. In Haparanda, an Olympus XQ-20 fiber endoscope (Olympus Co., Tokyo, Japan) was used; in Kalix, an Olympus GIF-100 videoendoscope (Olympus Co.) was used. To achieve endoscopic assessment reliability, the endoscopists participated in training sessions focusing on assessment of BE and esophagitis. 19,22 The gastroesophageal junction was defined as the junction of the proximal gastric folds and the tubular esophagus. In addition, hiatus hernia was recorded in the predefined protocol. Definitions of BE, Esophagitis, and Reflux Symptoms At endoscopy, BE was searched for when a suspected columnar-lined esophagus (CLE) was identified based on salmon-pink mucosa in either a circumferential upward shift of

3 December 2005 BARRETT S ESOPHAGUS IN THE GENERAL POPULATION 1827 the squamocolumnar junction or in adjacent mucosal tongues 3,14 or islands. 23 The diagnosis of BE was based on the endoscopic finding of suspected CLE in the distal esophagus, confirmed by the presence of SIM in the esophageal biopsy specimens. 1,2,24 It was defined as long-segment BE (LSBE) if the segment was 2 cm long and short-segment BE (SSBE) if it was 2 cm Furthermore, esophageal mucosal breaks (esophagitis) were graded according to the Los Angeles classification system. 28,29 Gastroesophageal reflux symptoms were defined as troublesome heartburn and/or acid regurgitation over the past 3 months. 22,30 Biopsy Specimens According to the protocol, at least 2 biopsy specimens were taken from the following locations in the esophagus: 2 cm above the Z-line, at the Z-line, and with an inverted endoscope at the cardia adjacent to the Z-line, with the aim of obtaining both squamous and columnar epithelium in the biopsy specimens from the last 2 locations. In addition, 2 or more biopsy specimens were taken from any suspected CLE areas. In the stomach, biopsy specimens were obtained according to the recommendations of the updated Sydney System 31 and for culture of H pylori. Biopsy specimens were independently examined by 2 experienced gastrointestinal pathologists (M.V. and M.S.) who were blinded to the clinical data and endoscopic findings. Biopsy specimens were stained with H&E, and those from the stomach were also stained with Warthin Starry silver stain. The diagnosis of BE was made only if SIM characterized by the presence of goblet cells could be identified. Complete intestinal metaplasia 32 of the cardia mucosa was not included in the definition. Histologic features of the gastric mucosa, such as inflammation and atrophy, were recorded and scored according to the updated Sydney System. 31 For identification of H pylori, histology and culture were used (for details, see Storskrubb et al 33 ). The subject was considered to have a current infection if histology and/or culture detected the bacteria. Laboratory Analysis Blood samples were taken for assessment of H pylori serology. H pylori antibodies of immunoglobulin G were determined by enzyme immunoassay (Pyloriset EIA-G; Orion Diagnostica, Espoo, Finland) at the Institute for Infectious Disease Control (Stockholm, Sweden). 33 Statistics P values were all 2 tailed, and the level of significance was set at The prevalence is shown as a percentage with a 95% confidence interval (CI). Fisher exact test and likelihood ratio 2 test were used for testing comparison in univariate analyses. Correlations were tested with the Spearman correlation test. Due to the low number of cases of BE, it was analyzed using Fisher exact test and a univariate logistic regression model adjusted for age (dichotomized at 50 years) and sex. 34 The results are shown as odds ratios (ORs) with 95% CIs. The reference group was given an OR of 1. The goodness of fit of the models was judged from the Pearson 2 test and degrees of freedom, which should be about equal. The fit of the model was considered to be acceptable with P.05. Age was tested for linearity. The Intercooled Stata 8 program 35 was used for the analyses. Age; sex; hiatus hernia; esophagitis; obesity 36 ; reflux symptoms; alarm symptoms (weight loss, dysphagia, anemia, hematochezia); use of tobacco (smoking or snuff); use of alcohol; use of nonsteroidal anti-inflammatory drugs or aspirin; use of antacids/alginates, H 2 -receptor antagonists, or proton pump inhibitors; current H pylori infection; serologic scar but no current infection with H pylori 33 ; chemical gastritis; atrophy of corpus or antrum mucosa; corpus-dominant H pylori gastritis; and education were included in the models as possible positive or negative risk factors for BE. Results Endoscopy Suspected CLE was found in 103 cases (10.3%; mean age, 55.7 years; 60.2% men). Twelve of them (1.2%) with a mean age of 59 years (7 men) had a long segment. Of the 87 suspected CLE cases without SIM in the biopsy specimens, there were 83 cases with columnar epithelium, 3 with squamous epithelium, and 1 with missing biopsy specimens. Hence, 96.1% of the suspected CLE had columnar epithelium in the biopsy specimens. On biopsy specimens from the distal esophagus and gastroesophageal junction, 60 were positive for SIM in total. Esophagitis was found in 155 cases (109 Los Angeles grade A, 39 grade B, 3 grade C, and 2 grade D; missing classification in 2 cases). BE BE was found in 16 individuals (1.6%) with a mean age of 57 years (9 men). LSBE occurred in 5 individuals (0.5%) with a mean age of 58 years, and 3 (60%) were men. SSBE occurred in 11 individuals (1.1%) with a mean age of 56 years, and 6 (54.6%) were men (Table 1). The age distribution by sex is shown in Table 2. The mean age of the men with BE was 52.2 years (5 of 9 younger than 50 years of age) compared with the mean age of 63 years for women with BE (6 of 7 older than 50 years of age). An endoscopic finding of suspected CLE was correlated to the histologic finding of SIM (Spearman 0.14; P.01). The prevalence of SIM in the esophageal biopsy specimens was higher if the length of the sus-

4 1828 RONKAINEN ET AL GASTROENTEROLOGY Vol. 129, No. 6 Table 1. Prevalence of BE and Prevalence of Gastroesophageal Reflux Symptoms and Esophagitis With BE or Without BE BE LSBE SSBE No BE No. of cases (%) 16 (1.6) 5 (0.5) 11 (1.1) 984 (98.4) % with gastroesophageal reflux symptoms % with esophagitis NOTE. n pected CLE was longer: 41.7% in segments 2 cm, 12.1% in segments 2 cm, and 4.5% without a visible suspected CLE segment (P.01 in segments 2 cmvs segments 2 cm,p.01 in segments 2 cmvsno visible segment, and P.01 in segments 2 cmvsno visible segment, respectively). Suspected CLE was not statistically significantly associated with reflux symptoms reported daily, weekly, or at any time during the 3 months before endoscopy. There was no difference in the prevalence of endoscopically suspected CLE (P.93), histologically diagnosed SIM (P.70), or confirmed BE (P.99) between the 2 endoscopy units. Predictors for BE The prevalence of BE in those with reflux symptoms was 2.3% and in those without, it was 1.2% (P.18). In those with esophagitis, the prevalence was 2.6% and in those without, it was 1.4% (P.32). The grading of esophagitis was not statistically significantly associated with BE; of the 16 subjects with BE, 4 had mild (Los Angeles grade A or B) and none had severe (grade C or D) esophagitis (P 1.0). H pylori colonization by histology, culture, and/or serology was present in 6 subjects (38%) with BE (and comparable to the EGD study sample [432/1000; 43%; P.64]) and in 26 of 60 subjects with SIM (43%; P 1.0). In the analysis by Fisher exact test, increased alcohol use ( 50 g absolute alcohol per week) was a risk factor for BE (P.04). Esophagitis (P.03) and hiatus hernia (P.01) were statistically significantly associated with LSBE, while alcohol (P.01) and smoking (P.01) were statistically significantly associated with SSBE. The distribution of predictors for BE, no BE, and suspected CLE with 95% CIs is shown in Table 3. In univariate analyses by logistic regression adjusted for age and sex, alcohol (OR, 3.0; 95% CI, ), and smoking (OR, 2.87; 95% CI, ) were statistically significant risk factors for all BE. In the same analysis, esophagitis (OR, 8.3; 95% CI, ) and hiatus hernia (OR, 13.0; 95% CI, ) were statistically significant risk factors for LSBE and alcohol (OR, 5.8; 95% CI, ) and smoking (OR, 5.9; 95% CI, ) were statistically significant risk factors for SSBE. Discussion Within the framework of a population-based study using endoscopy, we have examined the prevalence of BE and associated risk factors. The cohort represents a random unselected adult population. We found that the prevalence of BE was 1.6% (LSBE, 0.5%; SSBE, 1.1%). This prevalence of BE is in accordance with recently reported prevalence figures in large selected cohorts. 15,16 The prevalence of LSBE (0.5%) is also only modestly higher than that reported in the 1990 study by Cameron et al, in which it was about 0.34% (336/100,000). 14 Although Gerson et al and Rex et al have reported significantly higher prevalence rates of BE in selected cohorts (25% and 6.8%, respectively), 17,18 we found a notably lower prevalence of BE in the adult general population. We conclude that selection bias is most likely to account for the very high prevalence of BE observed in these studies. Our study has a number of limitations, including the fact that it does not allow the unambiguous assignment of cause and effect. We have shown earlier that this population appears representative of a true random sample of an adult population in 2 neighboring Swedish communities. 19 The mean age of subjects who underwent endoscopy was about 4 years greater than that of the original study population and of the Swedish population in the selected age band due to a lower participation rate among the youngest age group. Only among those younger than 35 years of age was there a significant overreporting of gastroesophageal reflux symptoms, 19 and this youngest age group is of less interest from the BE point of view because of the age distribution found. Thus, these age differences per se are most probably irrelevant for the interpretation of our results. Similarly, the exclusion of the 140 subjects who were not eligible for study at the time of approach did not alter the mean Table 2. Prevalence of BE by Age Group and Sex Age group (y) Older than 65 Total Men Women Total

5 December 2005 BARRETT S ESOPHAGUS IN THE GENERAL POPULATION 1829 Table 3. Prevalence of Predictors for BE, No BE, and Suspected CLE Predictors BE (n 16) No BE (n 984) Suspected CLE a (n 87) Mean age, (y) Men 56.3 ( ) 48.7 ( ) 60.1 ( ) Gastroesophageal reflux symptoms 56.3 ( ) 39.7 ( ) 47.1 ( ) Hiatus hernia 37.5 ( ) 23.7 ( ) 41.4 ( ) Esophagitis 25.0 ( ) 15.3 ( ) 29.9 ( ) Obesity 12.5 ( ) 16.2 ( ) 17.2 ( ) Smoking 37.5 ( ) 18.3 ( ) 24.1 ( ) Use of Alcohol 50 g/wk 50.0 ( ) 25.5 ( ) 27.6 ( ) Use of nonsteroidal anti-inflammatory drugs 6.3 ( ) 6.9 ( ) 5.7 ( ) Use of aspirin ( ) 13.8 ( ) Use of H 2 -receptor antagonists ( ) 3.4 ( ) Use of proton pump inhibitors 12.5 ( ) 4.8 ( ) 9.2 ( ) H pylori infection 31.3 ( ) 33.9 ( ) 35.6 ( ) Dysphagia 6.3 ( ) 6.8 ( ) 6.9 ( ) NOTE. Values are expressed as percentage (95% CI) unless otherwise noted. a Without SIM in the esophageal biopsy specimens. age and sex distribution of the remaining eligible group. Hence, we consider that there was no significant selection bias apparent except possibly for the youngest age group. The use of 3 different observers for endoscopy could be considered as a potential weakness in the study. Therefore, the endoscopists took part in training sessions for landmarks at EGD 37 and endoscopic diagnosis 23 and were tested for concordance to minimize the interobserver variation. 22 The use of fiber endoscopes in one third of the cases could have induced underestimation of BE. However, it did not seem to bias the results. There was neither a difference in the prevalence of BE as diagnosed by fiber endoscope versus that diagnosed by videoendoscope (1.6% vs 1.6%; P.99) nor in the endoscopic diagnosis of suspected CLE (P.93) or histologic diagnosis of SIM (P.70) between the 2 endoscopy units. The histologic evaluation was performed by experienced pathologists with a special interest in gastrointestinal pathology and BE, and the endoscopy and biopsy programs were performed according to a predefined protocol by experienced endoscopists. A once-in-a-lifetime endoscopy has been debated for subjects with chronic reflux symptoms to identify BE and try to reduce the risk of adenocarcinoma, but it is still controversial whether and when this should be performed. 3,38 The prevalence of reflux symptoms in BE was higher than that of non-be subjects, but this was not statistically significant in the present study, probably due to the low number of BE cases (56.3% in BE vs 39.7% in no BE). The prevalence was even more notable in LSBE (80% with reflux symptoms; Table 1). We have shown earlier that one third of those with esophagitis (15.5% of the same population) had no reflux symptoms and about two thirds of those with reflux symptoms had no esophagitis, although reflux symptoms were statistically significantly associated with esophagitis (P.01). 22 Because 43.7% of those with BE had no reflux symptoms and the prevalence overall was low, this suggests that screening based on reflux symptoms may be inadequate to detect BE. Alcohol (P.04) and smoking (P.047) were independent risk factors for BE, and esophagitis (P.03) and hiatus hernia (P.01) were statistically significantly associated with LSBE; these have also been found to be associated with BE by other studies Male sex has been shown to be a risk factor for both BE 40,43 and adenocarcinoma 44 of the esophagus. In this study, there were more men presenting with BE, although this was not statistically significant. Interestingly, 5 of the 9 men were younger than 50 years of age whereas 6 of the 7 women with BE were older than 50 years of age, although the low number failed to show a statistically significant sex difference. Because the mean age of men with BE was 10 years lower than that of women (52.2 and 63 years, respectively), this could perhaps indicate that men get the condition earlier and thus have more time to develop adenocarcinoma in the esophagus. However, the incidence of developing adenocarcinoma in BE was 1 in 208 patient-years in a prospective US study among men 45 ; in a recent Dutch study, the incidence was 1 in 221 for LSBE, which equals 0.45% per year, and there was no sex difference. 46 Use of aspirin has been shown to be associated with less esophageal adenocarcinoma. 47,48 Although 29.5% of the individuals with SIM in the esophageal biopsy specimens took acetylsalicylic acid (data not shown) com-

6 1830 RONKAINEN ET AL GASTROENTEROLOGY Vol. 129, No. 6 pared with 10.7% of the EGD study sample (P.01), it is notable that there were none in the BE (suspected CLE with histologically confirmed SIM in the esophageal biopsy specimens) group taking acetylsalicylic acid, and only 1 individual was taking nonsteroidal anti-inflammatory drugs. Further research in representative samples of the general population would be needed to confirm our prevalence rates against the higher ones in the selected US samples. 17,18 There are, however, practical dilemmas due to the low prevalence of BE. In conclusion, BE was found in 1.6% of the general adult population in Sweden. Alcohol and smoking were found to be statistically significant risk factors. References 1. Spechler SJ. The columnar-lined esophagus. History, terminology, and clinical issues. Gastroenterol Clin North Am 1997;26: Hirota WK, Loughney TM, Lazas DJ, Maydonovitch CL, Rholl V, Wong RK. 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