Relationship between Kyphosis and Barrett s Esophagus in Japanese Patients

ORIGINAL ARTICLE Relationship between Kyphosis and Barrett s Esophagus in Japanese Patients Goichi Uno 1, Yuji Amano 1, Takafumi Yuki 1, Akihiko Oka 2, Norihisa Ishimura 2, Shunji Ishihara 2 and Yoshikazu Kinoshita 2 Abstract Background Kyphosis is a risk factor for the presence of hiatal hernia, which is a strong predictor of Barrett s esophagus. However, the association between kyphosis and Barrett s esophagus has not yet been clarified. To investigate this relationship, the Cobb angle, a marker of kyphosis, was measured in patients with and without Barrett s esophagus. Methods From January 2006 to December 2010, 26 patients with long-segment Barrett s esophagus (LSBE) were retrospectively enrolled. As the comparative groups, 100 consecutive patients with shortsegment Barrett s esophagus (SSBE) and 100 consecutive control patients without Barrett s esophagus were also enrolled in this study. Cobb angles were measured on lateral chest radiographs, and kyphosis was defined as a Cobb angle of greater than 50. Kyphosis, along with other patient characteristics, were evaluated as possible predictors for SSBE and LSBE. Results The mean Cobb angles in the non-be, SSBE, and LSBE groups were 31.6 (95% CIs, 29.3-33.9 ), 34.8 (32.1-37.4 ) and 49.4 (44.9-53.9 ), respectively. Statistically significant differences were found between the LSBE and the other 2 groups (p<0.001). The mean Cobb angles were 33.3 ±12.4 and 37.0 ±14.1, respectively in patients without and with hiatal hernia (p=0.039). Predictors for Barrett s esophagus of any length were erosive esophagitis and hiatal hernia. Kyphosis had the highest odds ratio for the presence of LSBE (OR, 1.50; 95% CI, 1.05-1.94; p=0.033). Other predictors were hiatal hernia and the absence of Helicobacter pylori infection. Conclusion Kyphosis is a risk factor for the presence of LSBE in Japanese patients. Key words: kyphosis, Barrett s esophagus, hiatal hernia, Cobb angle (Intern Med 50: 2725-2730, 2011) () Introduction The incidence of Barrett s adenocarcinoma arising from Barrett s esophagus has been rapidly increasing in many Western countries over the past few decades (1-3). Therefore, the establishment of appropriate clinical management for Barrett s esophagus with high malignant potential is an important objective. Long segment Barrett s esophagus (LSBE) with intestinal metaplasia has been thought to have a high risk for the development of adenocarcinomas. Therefore, identification of the clinical markers of LSBE is necessary. We saw a patient with Barrett s ulcer and concurrent kyphosis. In this case, nocturnal reflux of gastric acid was thought to be important not only for the formation of Barrett s ulcer on the posterior wall of the esophagus, but also for the development of LSBE (4). Kyphosis mainly develops from osteoporosis-related wedging and/or the collapse of vertebral bodies, and is frequently found in the Japanese elderly. Kyphosis has been reported to be a risk factor for the presence of esophageal hiatal hernia (5, 6) which is a strong risk factor for Barrett s esophagus (7-10). Thus, kyphosis may have some association with Barrett s esopha- Division of Endoscopy, Shimane University Hospital, Japan and The Second Department of Internal Medicine, Shimane University, Faculty of Medicine, Japan Received for publication July 14, 2011; Accepted for publication August 11, 2011 Correspondence to Dr. Yuji Amano, amano@med.shimane-u.ac.jp 2725

Figure 1. Calculation method for Cobb angle. Lines were drawn along the plane of the superior endplate of T4 and the inferior endplate of T12 and the angles between their intersection or between angles of intersecting lines drawn perpendicular to them were measured using a protractor. Kyphosis was defined as an angle of greater than 50. gus and might be used as a clinical sign of the presence of Barrett s esophagus and its associated cancer risk. However, there are few studies that have investigated the relationship between kyphosis and Barrett s esophagus, and we therefore undertook a study to investigate the association between kyphosis and Barrett s esophagus. Patients and Methods Thirty-two patients with LSBE were endoscopically diagnosed at Shimane University Hospital from January 2006 to December 2010. Twenty-six out of 32 whose chest radiographic examinations were sufficient for the diagnosis of kyphosis were enrolled in the present study. Therefore, two patients with apparent kyphosis and four without kyphosis were excluded. As the comparative groups, 100 consecutive patients with short segment Barrett s esophagus (SSBE) and 100 consecutive control patients without Barrett s esophagus were also enrolled. Chest radiographic examinations of the enrolled patients were done to examine for cardiopulmonary problems or as an annual check-up for lung diseases. In each patient, both the front and lateral views were examined by digital radiographic system, and the lateral chest radiographic image was digitally adjusted to evaluate their vertebral form via the gain and contrast controller. As shown in Fig. 1, the Cobb angle was measured using the following procedures: lines were drawn along the plane of the superior endplate of T4 and the inferior endplate of T 12 and the angles between their intersection or between angles of intersecting lines drawn perpendicular to them were measured using a protractor. A patient was considered to have kyphosis if the measured Cobb angle was greater than 50 (11, 12). Barrett s esophagus was diagnosed endoscopically if columnar-appearing mucosa was observed between the squamocolumnar and the esophagogastric junction. The esophagogastric junction was defined as the proximal margin of the gastric folds, and the length of Barrett s esophagus was classified based on the Prague C and M criteria (13, 14). In the present study, endoscopically detected columnar-appearing mucosa was diagnosed as endoscopic Barrett s esophagus if the mucosa was longer than 1 cm (M: 1.0) in length. Barrett s esophagus of greater than 3 cm (C: 3.0) in length was defined as LSBE and that of less than 3 cm was defined as SSBE. The grade of reflux esophagitis, the presence of hiatal hernia and gastric mucosal atrophy were determined during the endoscopic study. Reflux esophagitis was endoscopically graded by the Los Angeles classification (15). Erosive esophagitis was diagnosed when demarcated mucosal breaks were found in the lower esophagus. The grades consist of A, B, C and D; A: mucosal break no longer than 5 mm that only extend on one fold, B: mucosal break longer than 5 mm that only extend on one fold, C: mucosal break that is continuous between two or more folds (less than 75% of the circumference), D: mucosal break which involves at least 75% of the esophageal circumference. Esophageal hiatal hernia was diagnosed when over 2 cm of the dislocation of esophago-gastric junction toward the esophageal site was endoscopically found (16). The extension of gastric mucosal atrophy was determined by the position of the endoscopic atrophic border, the borderline between fundic and pyloric gland area. It was classified as closed (C-I, C-II and C-III) and open types (O-I, O-II, O- III) (17). The open type of gastric mucosal atrophy was judged when the atrophic border was not found in the lesser curvature of the upper corpus. This grading system was confirmed to be closely related with gastric acid secretion capability. Helicobacter pylori infection was detected by the rapid urease test, serology, or the 13 C urea breath test. Chronic usage of proton pump inhibitors (PPIs) over 6 months such as omeprazole (20 mg/day), lansoprazole (30 mg/day), or rabeprazole (10 mg/day) was also investigated. The protocol of this study was prepared according to the Declaration of Helsinki and approved by the ethics committee of Shimane University School of Medicine. Statistical analysis Categorical data were compared by the chi-square test or Student s t-test. The Cobb angles of each group were compared using the Wilcoxon signed-rank test if the Friedman test showed significant differences. The relationship between Cobb angle and hiatal hernia was also assessed by Student s t-test. Data were subjected to multivariate logistic regression analysis to determine predictors for the presence of Barrett s esophagus and for LSBE. Independent predictors were expressed as relative risk and 95% confidence intervals (CI). Predictors for LSBE were also analyzed by the age and gender matched-pair comparison with control and SSBE groups. P-values less than 0.05 were considered significant. All sta- 2726

Table 1. Patient Characteristics of Enrolled Patients Non-BE (n = 100) SSBE (n = 100) LSBE (n = 26) Age 68.3±11.3* 70.0±10.5 # 78.2±9.0 Gender (male, %) 51.0** 66.0 73.0 H. pylori infection (%) 70.0* 69.0 ## 11.5 PPI administration (%) 11.0* 23.0 ## 46.1 Erosive esophagitis (%) 3.0** 8.0 15.3 Gastric mucosal atrophy (%) 41.0** 59.0 # 7.6 Hiatal hernia (%) 26.0* 55.0 ## 80.7 BE: Barrett s esophagus, SSBE: short-segment Barrett s esophagus, LSBE: long-segment Barrett s esophagus, PPI: proton pump inhibitor LSBE vs. Non-BE: *, p < 0.001; **, p < 0.05 LSBE vs. SSBE: #, p < 0.001; ##, p < 0.05 Figure 2. Mean Cobb angles are shown. The mean Cobb angle of long-segment Barrett s esophagus (LSBE) patients was significantly larger than the angles of non-barrett s esophagus (non-be) and short-segment (SS) BE patients. Circles show mean values. Bars depict 95% confidence intervals. * p < 0.001; ** p = 0.001. Figure 3. Relationship between hiatal hernia (HH) and Cobb angle. The mean Cobb angle in patients with hiatal hernia (HH+) was significantly larger than the angle in those without hiatal hernia. Bars depict standard errors. * p = 0.039. tistical analyses were performed using statistical analysis software (IBM SPSS Statistics 18; SPSS Japan Inc., Tokyo, Japan). Results Characteristics of the 3 groups of enrolled patients are shown in Table 1. Patients with LSBE were older, and there was a higher prevalence of erosive esophagitis and hiatal hernia, and a lower prevalence of Helicobacter pylori infection and gastric mucosal atrophy than in the non-be and SSBE groups. Kyphosis (Cobb angle>50 ) was seen in 3 (3.0%), 7 (7.0%), and 10 (38.4%) patients of the non-be, SSBE, and LSBE groups, respectively. The mean Cobb angles were 31.6 (95% CI, 29.3-33.9 ), 34.8 (32.1-37.4 ) and 49.4 (44.9-53.9 ) in the non-be, SSBE, and LSBE groups, respectively (Fig. 2). The differences between the LSBE and each of the other groups were significant (p<0.001). There was no statistically significant difference between the non- BE and SSBE groups. The relationships between the Cobb angle and hiatal hernia are shown in Fig. 3. The mean Cobb angles were 33.3 ±12.4 (mean ± SD) and 37.0 ±14.1, in the groups without and with hiatal hernia, respectively, and the difference was statistically significant (p=0.039). Multivariate analysis determined that the predictors for the presence of Barrett s esophagus of any length (both short- and long-segment) included the presence of erosive esophagitis (odds ratio [OR] 2.06; 95% CI 1.01-4.75; p= 0.029) and hiatal hernia (OR 1.07; 1.01-1.32; p=0.001), although the presence of kyphosis did not correlate with the presence of Barrett s esophagus (p=0.207) as shown in Table 2. Independent predictors for the presence of LSBE were shown in Table 3. Kyphosis had the highest odds ratio for LSBE (OR 1.50; 1.05-1.94; p=0.033). Another positive predictor was hiatal hernia (OR 1.24; 1.02-2.21; p=0.021), and a negative predictor was Helicobacter pylori infection (OR 0.86; 0.35-0.93; p=0.002). The presence of gastric mucosal atrophy showed a negative odds ratio (0.30), but the value did not reach statistical significance (p=0.053). After the categorical data of age and gender were paired in control and SSBE groups against LSBE group, 52 patients in control and SSBE groups were compared with 26 LSBE group (1:2 comparisons). Matched-pair patient s char- 2727

Table 2. Predictors for Barrett s Esophagus of Any Length (Short and Long Segment) Predictors Odds ratio (95% CI) p value Age 1.01 (0.96-1.07) 0.585 Gender (male) 0.94 (0.26-3.31) 0.957 H. pylori infection (yes) 1.05 (0.26-4.17) 0.938 PPI administration (yes) 0.78 (0.42-2.89) 0.567 Erosive esophagitis (yes) 2.06 (1.01-4.75) 0.029 Gastric mucosal atrophy (yes) 1.40 (0.61-9.40) 0.206 Hiatal hernia (yes) 1.07 (1.01-1.32) 0.001 Kyphosis (yes) 1.29 (0.44-1.96) 0.207 Kyphosis (yes): Cobb angle > 50º, PPI: proton pump inhibitor Table 3. Predictors for Long-segment Barrett s Esophagus Predictors Odds ratio (95% CI) p value Age 0.94 (0.86-1.02) 0.153 Gender (male) 1.29 (0.52-6.25) 0.430 H. pylori infection (yes) 0.86 (0.35-0.93) 0.002 PPI administration (yes) 0.98 (0.31-5.36) 0.865 Erosive esophagitis (yes) 1.19 (0.53-2.90) 0.235 Gastric mucosal atrophy (yes) 0.30 (0.09-1.01) 0.053 Hiatal hernia (yes) 1.24 (1.02-2.21) 0.021 Kyphosis (yes) 1.50 (1.05-1.94) 0.033 Kyphosis (yes): Cobb angle > 50º, PPI: proton pump inhibitor Table 4. Patient s Characteristics of Matched-pair Analysis Non-BE (n = 52) SSBE (n = 52) LSBE (n = 26) Age 78.2±8.8 78.2±8.8 78.2±9.0 Gender (male, %) 73.0 73.0 73.0 H. pylori infection (%) 76.9* 57.6 ## 11.5 PPI administration (%) 5.7* 38.4 ## 46.1 Erosive esophagitis (%) 5.7 7.6 15.3 Gastric mucosal atrophy (%) 61.5* 38.4 # 7.6 Hiatal hernia (%) 28.8* 55.7 ## 80.7 BE: Barrett s esophagus, SSBE: short-segment Barrett s esophagus, LSBE: long-segment Barrett s esophagus, PPI: proton pump inhibitor LSBE vs. Non-BE: *, p < 0.001; **, p < 0.05 LSBE vs. SSBE: #, p < 0.001; ##, p < 0.05 acteristics are shown in Table 4. Prevalence of H. pylori infection and gastric mucosal atrophy were lower, although hiatal hernia was more frequently found in LSBE group. Table 5 revealed the independent predictors for LSBE in the matched-pair analysis. Absence of H. pylori infection (OR 0.30; 0.03-0.86; p=0.006) and the presence of hiatal hernia (OR 6.25; 2.11-11.32; p=0.030) and presence of kyphosis (OR 22.13; 1.01-481.49; p=0.049) were predictors. Discussion In this study, the Cobb angle was associated with the presence of hiatal hernia, as previously reported by Kusano et al (5, 6); and a high prevalence of kyphosis was only found in patients with LSBE but not in patients with SSBE, although hiatal hernia is known to be closely associated with both LSBE and SSBE. McMillan and Hyde reported that the esophagus fell back into the concavity of the kyphotic curve, with forward pressure being exerted by secondary distal lordosis. Accordingly, in the supine position, the thoracic esophagus of kyphotic patients is located lower than the stomach, which exacerbates hiatal hernia (18). In patients with kyphosis, gastroesophageal reflux is easily induced, not only in the supine but also in the upright position, and the reflux tends to remain in the esophagus during the supine position at night, which reflects the close relationship between kyphosis and the development of Barrett s esophagus, since nocturnal acid and bile reflux are thought to play an important role in the pathogenesis of Barrett s esophagus (19). Some investigators have reported that an increased Cobb angle induced by numerous fractures of the lumbar vertebrae may be important risk factors for gastroesophageal reflux disease in patients with osteoporosis (20, 21). Yoshimura et al also reported that the presence of vertebral fractures is significantly associated with the presence of either erosive esophagitis or hiatal hernia (22). Yamaguchi et al have demonstrated that there is a positive association between multiple vertebral fractures and refractory erosive esophagitis (23). Therefore, kyphosis in the elderly may be an important risk factor for the development of Barrett s esophagus (24). It was interesting that in our study there was a male preponderance in the LSBE group compared to the proportion of males in the SSBE group. In Japan, kyphosis is more prevalent in female patients than in males (6, 21-23). Only 27% of the patients with LSBE were female in this study. Male gender is considered to be a risk factor for LSBE, but not for SSBE. Therefore, there may be different pathogenic mechanisms involved in LSBE and SSBE. As already mentioned, kyphosis is considered to be a risk factor for the occurrence of pathological gastroesophageal reflux. In the present study, we found a statistically significant positive correlation between the presence of LSBE and kyphosis. The kyphosis-related gastroesophageal reflux and impaired clearance of gastric contents, in particular that from the mid and proximal esophagus, likely play roles in the development of LSBE. As an additional factor, longterm administration of PPI for the symptomatic treatment of LSBE may decrease calcium absorption and may increase the risk of osteoporosis with the development of kyphosis (25, 26). Although the mechanism is not yet clarified, we 2728

Table 5. Predictors for Long-segment Barrett s Esophagus by Matched-pair Analysis Predictors Odds ratio (95% CI) p value Age 0.92 (0.83-1.03) 0.175 Gender (male) 0.88 (0.09-9.61) 0.917 H. pylori infection (yes) 0.30 (0.03-0.86) 0.006 PPI administration (yes) 2.78 (0.20-38.63) 0.445 Erosive esophagitis (yes) 15.06 (0.20-110.75) 0.216 Gastric mucosal atrophy (yes) 0.83 (0.25-3.01) 0.213 Hiatal hernia (yes) 6.25 (2.11-11.32) 0.030 Kyphosis (yes) 22.1 (1.01-481.49) 0.049 PPI: proton pump inhibitor have shown the positive correlation between kyphosis and the presence of LSBE in the present study. There are some limitations to this study. First, the number of patients with LSBE was small and they were studied retrospectively. LSBE is less prevalent in the Japanese population compared to other groups; investigators have reported that the prevalence of LSBE in Japan is 0.2%- 0.5% (9, 10, 24). Therefore, a prospective Japanese multicenter study with a larger number of LSBE patients is needed. 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27. Perkins AC, Frier M, Blackshaw PE, et al. Esophageal transit of the weekly film-coated risedronate (Actonel) placebo tablet in subjects with kyphosis. Int J Pharm 311: 20-25, 2006. 2011 The Japanese Society of Internal Medicine http://www.naika.or.jp/imindex.html 2730