Original Articles

Juntendo Medical Journal 2018. 64(2), 108-113 Predictive Ability for Reflux Esophagitis by Gastroesophageal Barium Reflux and Angle of His Seen in Upper Gastrointestinal Series

TAKAYUKI HASHIMOTO＊1) 2),KOUTATSU MARUYAMA＊1) 3),YOSHIO YAMAJI＊1) 4),

HIROO WADA＊1),AI IKEDA＊1),KOU MORICHIKA＊5),TAKESHI TANIGAWA＊1)

＊1)Department of Public Health, Juntendo University Graduate School of Medicine, Tokyo, Japan, ＊2)Yushikai Nogi Hospital, Tochigi, Japan, ＊3)Laboratory of Community Health and Nutrition, Special Course of Food and Health Science, Department of Bioscience, Ehime University Graduate School of Agriculture, Ehime, Japan, ＊4) Life-Care Clinic Nozomi, Tochigi, Japan, ＊5)Ochanomizu-Sougo Clinic, Tokyo, Japan

Objective: This study aimed to examine the ability of barium-confirmed gastroesophageal reflux and the angle of His assessed using upper gastrointestinal series (UGIS) to predict the presence of reflux esophagitis (RE). Design: A total of 1,628 middle-aged Japanese individuals who underwent a radiographic and endoscopic examination between January 2000 and December 2012 were recruited. Methods: The receiver operating characteristic (ROC) curves and the area under the curves (AUCs) were used for RE diagnosis according to barium reflux, the angle of His, and their combination. The predictive sensitivity, specificity, and the Youden index were calculated according to the combination of the two indices, and the maximum value of the Youden index was considered as the optimal cutoff value for RE diagnosis. Results: ROC analysis was performed to estimate the optimal cutoff values of the Youden index for barium reflux and the angle of His. The AUCs for RE diagnosis according to barium reflux, the angle of His, and their combination were 0.76, 0.64, and 0.80, respectively. The optimal cutoff value was an angle of His of 45-46°with barium reflux. The sensitivity, specificity, and the Youden index were 76.3%, 80.4%, and 0.56, respectively. Conclusion: Our results suggest that barium reflux and the angle of His assessed using UGIS are useful for an early diagnosis of RE. Key words: upper gastrointestinal series (UGIS), gastroesophageal reflux disease (GERD), reflux esophagitis (RE), angle of His

In contrast, the prevalence of RE in Japan was Introduction previously reported to be low, but has recently Endoscopic esophagitis typically involves reflux increased, and RE is currently regarded as an esophagitis (RE) 1) and is the primary finding of important medical issue 7). Therefore, itis important gastroesophageal reflux disease (GERD). GERD to develop early diagnostic and treatment methods involves the retrograde flux of gastric contents into for RE in the Japanese population. the esophagus, which stimulates the esophageal Various approaches, including questionnaires, the mucosa. proton pump inhibitor (PPI) test, endoscopy, upper Because RE is highly prevalentin Western gastrointestinal series (UGIS), and 24 h pH moni- countries and is known as a precancerous disease of toring, are used RE diagnosis; endoscopy is consid- the esophagus, esophageal screening is crucial 2)-6). ered as the standard diagnostic approach 8). UGIS is

Corresponding author: Takeshi Tanigawa Department of Public Health, Juntendo University Graduate School of Medicine 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan TEL: +81-3-5802-1048 FAX: +81-3-3814-0305 E-mail: [email protected] 〔Received July 21, 2017〕〔Accepted Oct. 26, 2017〕

Copyright © 2018 The Juntendo Medical Society. This is an open access article distributed under the terms of Creative Commons Attribution Li- cense (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original source is properly credited. doi: 10.14789/jmj.2018.64.JMJ17-OA10

108 Juntendo Medical Journal 64(2), 2018

less invasive and has a shorter examination time mucous membrane injury such as inflammation than endoscopy. Furthermore, UGIS with barium with a length of 5 mm or less; Grade B examinees contrast helps objectively visualize the gastroeso- exhibitedatleastone mucous membrane injury phageal morphology and gastroesophageal reflux with a length of 5 mm or longer but without (GER). The angle of His is determined as the adhesion over the injuries; Grade C examinees incident angle of the lower esophagus in the cardiac exhibited adhesion of mucous membrane injuries region with respect to the stomach on UGIS 9), and it over 75% or less of the mucous circumference; and is associated with lower esophageal sphincter Grade D examinees cases exhibited adhesion of (LES) function 10)-12). Our previous studies 13) 14) mucous membrane injuries over 75% or more of the showed that the presence of barium-confirmed mucous circumference. Examinees without a GER and the larger angle of His are associated with mucous membrane injury were diagnosed as not a higher prevalence of esophagitis; however, the having RE. population was too small to perform statistical analysis. This led to a hypothesis that barium reflux 3. UGIS measurements and the angle of His, as assessed using UGIS, can UGIS was performed by a trained radiological predictthepresence of RE. technologist (TH) using an X-ray television system Therefore, the present study aimed to examine (KXO-50N, TOSHIBA, Tokyo, Japan), 120-180 ml the ability of barium reflux and the angle of His of a 180-220 w/v% high-density, low-viscosity using UGIS to diagnose RE among the Japanese barium contrast medium (Barytgen ®, FUSHIMI, individuals undergoing health checkup. Kagawa, Japan), and 5.0 g of a foaming agent (BAROS EFFERVESCENT GRANULES ®, HORII, Methods Osaka, Japan) for double contrast (sodium bicar- 1. Subjects bonate＋tartaric acid), in accordance with the New The study included 1, 231 male and 792 female Gastrointestinal X-ray Imaging Guidelines 17).No individuals who underwentUGIS as partof an examinees underwent pre-test treatment with an annual medical checkup attheOchanomizu-Sougo anticholinergic (scopolamine butylbromide) injec- Clinic between January 2000 and December 2012. tion. Body weight, height, and body mass index The examinees did not have severe gastrointestinal- (BMI) were measured at the time of UGIS. related diseases, i.e., gastric cancer, esophagus A radiological technologist confirmed the pres- varix, or esophageal achalasia. Those who did not ence of reflux in cases where X-ray films revealed undergo upper endoscopy (n=365) and those with the presence of barium reflux. Reflux of gastric a history of esophageal, stomach, or duodenal barium to the lower thoracic esophagus was surgery (n=30) were excluded. Therefore, data determined using double-contrast gastrography in from a total of 976 male and 652 female examinees the supine position (Figure-1) and a barium-filled were analyzed. The study was approved by the image in the prone position. Each UGIS examination Ethics Committee of Juntendo University (No. took approximately 10 min. 2015109). In the present study, the angle of His was defined as the angle at the cardiac notch formed by a 2. Diagnosis of RE tangent line connecting the angular part of the RE was diagnosed by a board certified gastroen- stomach with the gastric base in the cardia and terologist (KM) of the Japanese Society of Gastro- intersecting a line extending from the center of the enterology after an inquiry accompanying the lower esophageal transverse diameter to the center assessment of the upper gastrointestinal tract. KM of the esophageal hiatus in upright images of the graded the RE of all examinees using images barium-filled stomach (Figure-2). Measurements obtained through a GIF-Q200 9.8 mm endoscope were obtained by TH using a ruler and a (OLYMPUS ®, Tokyo, Japan) within 2 weeks after semicircular protractor. UGIS. The examinees were classified into grades ranging from A to D according to the Los Angeles 4. Statistical analysis classification 15) 16). Grade A examinees exhibited Mean differences in age, the angle of His, and BMI

109 Hashimoto, et al: Upper gastrointestinal series and reflux esophagitis

Angle of His

Figure-1 Barium-confirmed gastroesophageal reflux The reflux of gastric barium to the esophagus in the supine Figure-2 Angle of His position. The incident angle of the lower esophagus to the stomach is referred to as the angle of His.

were evaluated using Studentʼs t-test, and differen- 740 (45.5%) had barium reflux. In the presence of ces in sex distribution and the presence of barium barium reflux, increases in age, BMI, and the angle reflux between the RE and non-RE groups were of His were significantly associated with the compared using the Chi-square test. The presence severity of RE (date not shown). The RE group of RE according to barium reflux, quintiles of the included individuals who were older and had a angle of His, and their combination were evaluated higher mean BMI than those in the non-RE group. using receiver operating characteristic (ROC) Additionally, this group included a higher propor- analysis and the area under the curve (AUC). tion of male individuals and individuals with barium Furthermore, the prediction sensitivity and specif- reflux than those in the non-RE group (Table-1). icity and the Youden index 18) were calculated The ROC curves and AUCs for RE according to according to the combination of barium reflux barium reflux, the angle of His, and their combina- (binary variable) and quintiles of the angle of His. tion are shown in Figure-3. The AUCs for RE The maximum value of the Youden index was diagnosis according to barium reflux, the angle of regarded as the optimal cutoff value for the His, and their combination were 0.76, 0.64, and prediction of RE. All statistical analyses were 0.80, respectively. performed using SAS version 9.4 (SAS Institute The sensitivity, specificity, and the Youden index Inc., Cary, NC, USA), and the level of significance according to the combination of barium reflux and was two-sided p<0.05. quintiles of the angle of His are presented in Table-2. The presence of barium reflux and a larger Results angle of His tended to show high specificity. The mean (SD) age and BMI of all examinees According to the Youden index, the optimal cutoff were 57.9 (13.2) years and 22.5 (2.3) kg/m2, value was barium reflux with an angle of His of respectively. Of the 1,628 examinees, 524 (32.1%) 45-46°, with sensitivity, specificity, and the Youden were diagnosed with RE, Grade A (94.6%), Grade index of 76.3%, 80.4%, and 0.56, respectively. B (4.6%), Grade C (0.4%), Grade D (0.4%), and

110 Juntendo Medical Journal 64(2), 2018

Table-1 Clinical characteristics according to reflux esophagitis among 1,628 medical examinees RE (n=524) non-RE (n=1,104) p-value Gender, Male / Female 346/178 630/474 <0.01 Age, years 61.6±12.4 56.2±13.2 <0.01 BMI, kg/m2 23.3±2.7 22.2±2.1 <0.01 Barium reflux 423 (80.7) 317 (28.7) <0.01 Angle of His, degrees 53.9±11.4 48.3±11.9 <0.01

Age, BMI and angle of His were shown as mean± SD. Barium reflux was shown as number (%). p-value: Studenʼs t-test or Chi-square test

A Barium reflux B Angle of His C Barium reflux＋Angle of His 1.00 1.00 1.00

0.75 0.75 0.75

0.50 0.50 0.50 Sensitivity Sensitivity Sensitivity 0.25 0.25 0.25

0.00 0.00 0.00 0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00 1－Specificity 1－Specificity 1－Specificity Figure-3 ROC curves and AUC to detect RE according to barium reflux, angle of His and their combination The AUCs for RE diagnosis was 0.76 by barium reflux (A) and 0.64 by the angle of His (B). The AUC of the ROC curve for RE was 0.80 (C).

Table-2 Sensitivity, specificity, and youden index to detect reflux esophagitis according to the combination of barium reflux and angle of His Barium reflux (-) (+) Quintiles of His, -44° 45°-46° 48°-50° 52°-58° 60°- -44° 45°-46° 48°-50° 52°-58° 60°- degrees Sensitivity, % 100 97.5 93.1 89.5 84.9 80.7 76.3 61.2 41.6 23.4 Specificity, % 0 15.8 35.7 50.8 63.3 71.2 80.4 83.3 90.5 96.2 Youden index 0 0.13 0.28 0.40 0.48 0.52 0.56 0.44 0.32 0.19

of GERD (FSSG) were 62% and 59%, Discussion respectively 21). Additionally, the sensitivity and In this study, individuals with RE were more specificity of the PPI test, which is another less likely to have barium reflux and a greater angle of invasive method for diagnosing RE, were 75-80% His. According to the Youden index, the presence of and 55-74%, respectively 22) 23). Thus, the sensitivity barium reflux and an angle of His of 45-46°were and specificity of the PPI test were better than relatively sufficient to detect RE. those of the questionnaire. Our screening method Various esophagitis screening tools have been involving a combination, had better results and was developed, particularly for RE. Previous studies more appropriate because the PPI test is costlier have reported that the sensitivity and specificity of and requires consultation with clinicians. the Questionnaire for the Diagnosis of Reflux A useful method used to diagnose typical or Disease (QUEST) were 70-72% and 46-54% 19) 20), atypical RE without obvious mucosal injury to the and those of the Frequency Scale for the Symptoms esophagus is 24 h pH monitoring, and the AUC of

111 Hashimoto, et al: Upper gastrointestinal series and reflux esophagitis

the ROC curve, sensitivity, and specificity of this patient-based studies. Nevertheless, the limitations method were 0.89, 80%, and 81.2%, respectively 24). of this study should be discussed. First, there was a However, this method is impractical for use as a restriction with regard to the fluoroscopy time in screening testbecauseitrequires the24 h place- health checkup examination; thus, a detailed exami- ment of a catheter. Therefore, compared with the nation of hernias was difficult. With regard to hiatal aforementioned screening methods, this method, hernia, which is an important characteristic of which involves measurements of the angle of His GERD, we could not obtain appropriate images in all and barium reflux using UGIS, is an easy, less examinees. The second limitation was that a direct invasive, and practical approach for RE diagnosis. comparison of multiple modalities in RE detection Although barium reflux measured using UGIS was not possible because no other RE screening tool was defined as a surrogate index of GER in another was concomitantly used in the same examinee. study 25), our previous studies have indicated that UGIS is a major screening modality for digestive GER was not observed in some patients with organ diseases. According to a nation-wide survey RE 13) 14). Indeed, barium reflux was absentin 19% of by the Japanese Society of Gastrointestinal Cancer individuals with RE. In general, barium reflux Screening, approximately 6,800,000 individuals assessed using UGIS is only exclusively detectable annually undergo upper gastrointestinal tract for several seconds on fluoroscopic examination; examinations involving UGIS 31). UGIS offers excel- thus, barium reflux is not always found during lent accuracy and processing ability that has been examination, even in individuals with RE. However, established for over half a century, and it remains the sensitivity and specificity of barium reflux the most commonly used method to examine upper measurements using UGIS were found to be gastrointestinal tract in Japan. comparable to those of the other screening tools for In the present study, the prevalence of RE was RE diagnosis. 32.1%, and itwas nearly equivalenttothose Because transient relaxation is the primary reported in other studies on Japanese individ- mechanism underlying GER, the functional assess- uals 32) 33) that followed the original Los Angeles ment of LES, including the effects of movement of classification before revision. RE is a factor that the diaphragmatic crura on the lower esophagus, is increases the risk of precancerous diseases, and important 26). A previous study has reported that approximately 30% of Japanese adults are exposed the proportion of GER during LES relaxation is to this risk. Therefore, an early detection and the higher among GERD patients than among non- treatment of RE are important. Additional assess- GERD patients (34.0-65.0% vs. 13.0-35.0%) 27). ments of gastroesophageal barium reflux and the A previous study has described that interactions angle of His using UGIS will lead to an early of the angle of His, ring-shaped muscle of the diagnosis of RE. esophagus, oblique muscle of the stomach, cardiac In conclusion, we found that barium reflux and rosette, phrenoesophageal ligament, and diaphrag- the angle of His assessed using UGIS reasonably matic crura potentially influence LES pressure 28). predicted the presence of RE. Other studies have reported that destruction of the Conflicts of interest angle of His due to abdominal surgery results in functional impairment of the lower esophagus 29) 30). The authors have no conflicts of interest to Additionally, our previous study on approximately declare. 350 health checkup examinees showed that RE References individuals have a higher prevalence of barium reflux and a larger mean angle of His 13). Therefore, 1) Yakaji K: Reflux esophagitis, Esophageal ulcer. In: barium reflux and a large angle of His could be Fukui T, Takagi M, Komuro I, eds. Todayʼs Therapy 2014. Tokyo: Igakushoin, 2014: 444-446. (in Japanese) considered as major characteristics of RE. 2) Amano Y, Kinoshita Y: Strategy for diagnosis and The strength of this study is that it enrolled medical management of Barrettʼs esophagus. J Gastroen- annual checkup examinees without any manifesta- terol, 2005; 102: 160-169. (in Japanese) 3) Morichika K, Ishi K, Hashimoto T, Kusano M: Three tions; therefore, sampling bias was small and study cases of adenocarcinoma in Barrettʼ s epithelium in findings are generalizable compared with those of patients with reflux esophagitis. Juntendo Medical

112 Juntendo Medical Journal 64(2), 2018

Journal, 2007; 53: 306-309. (in Japanese) usefulness of a structured questionnaire in the assess- 4) Sharma P: Clinical practice. Barrettʼs esophagus. N Engl ment of symptomatic gastroesophageal reflux disease. J Med, 2009; 361: 2548-2556. Scand J Gastroenterol, 1998; 33: 1023-1029. 5) Haruma K, Honda K, Kamata T: Reflux esophagitis - 20) Inaba K, Kawai H, Kobara H, et al: The usefulness of a Japan and Western countries. Nihon Rinsho, 2004; 62: structured Questionnaire (QUEST) in the assessment of 1415-1419. (in Japanese) gastroesophageal reflux disease. J New Rem & Clin, 6) Fujimoto K: Review article: prevalence and epidemiol- 1999; 48: 1277-1289. (in Japanese) ogy of gastro-oesophageal reflux disease in Japan. 21) Kusano M, Shimoyama Y, Sugimoto S, et al: Develop- AlimentPharmacol Ther, 2004; 20 Suppl 8: 5-8. ment and evaluation of FSSG: frequency scale for the 7) GERD Society Study Committee: Ohara S, Kouzu T, symptoms of GERD. J Gastroenterol, 2004; 39: 888-891. Kawano T, Kusano M: Nationwide epidemiological 22) Johnsson F, WeywadtL, Solhaug JH, HernqvistH, survey regarding heartburn and reflux esophagitis in Bengtsson L: One-week omeprazole treatment in the Japanese. J Gastroenterol, 2005; 102: 1010-1024. (in diagnosis of gastro-oesophageal reflux disease. Scand J Japanese) Gastroenterol, 1998; 33: 15-20. 8) Fornari F, Wagner R: Update on endoscopic diagnosis, 23) Wang WH, Huang JQ, Zheng GF, et al: Is proton pump management and surveillance strategies of esophageal inhibitor testing an effective approach to diagnose diseases. World J Gastrointest Endosc, 2012; 4: 117-122. gastroesophageal reflux disease in patients with noncar- 9) Dittrich JK: Röntgenuntersuchungen über die Bedeu- diac chest pain?: a meta-analysis. Arch Intern Med, tung des sogenannten Hisschen Winkels für die Kardia- 2005; 165: 1222-1228. funktion bei Kindern. Eur J Pediatr, 1965; 94: 361-374. 24) Dinelli M, Passaretti S, Di Francia I, Fossati D, Tittobello 10) Iino M: Clinical study on abnormalities of lower esopha- A: Area under pH 4: a more sensitive parameter for the geal sphincter (LES) function in infancy and childhood quantitative analysis of esophageal acid exposure in with special reference to gastroesophageal reflux. Nihon adults. Am J Gastroenterol, 1999; 94: 3139-3144. Heikatsukin Gakkai Zasshi, 1990; 26: 107-121. (in Japa- 25) Thompson JK, Koehler RE, Richter JE: Detection of nese) gastroesophageal reflux: value of barium studies com- 11) Fujiwara Y, Nakagawa K, Kusunoki M, Tanaka T, pared with 24-hr pH monitoring. Am J Roentgenol, 1994; Yamamura T, Utsunomiya J: Gastroesophageal reflux 162: 621-626. after distal gastrectomy: possible significance of the 26) Dodds WJ, DentJ, Hogan WJ, et al: Mechanisms of angle of His. Am J Gastroenterol, 1998; 93: 11-15. gastroesophageal reflux in patients with reflux esophagi- 12) Kawa Y, Seshimo A, Kameoka S: A study on gastroeso- tis. N Eng J Med, 1982; 307: 1547-1552. phageal reflux disease (GERD) after distal gastrectomy. 27) Iwakiri K, Sakamoto C: Pathophysiology of gastroeso- Nihon Shokaki Geka Gakkai Zasshi, 2003; 36: 347-353. phageal reflux disease: motility factors. Nihon Shokaki- (in Japanese) byo Gakkai Zasshi, 2003; 100: 1084-1094. (in Japanese) 13) Hashimoto T, Kusano M: Obesity and reflux esophagitis. 28) Maki T, Shiratori T, Okabayashi T: Postoperative Juntendo Medical Journal, 2002; 48: 323. (in Japanese) regressive esophagitis. J Clinical Surg, 1966; 21: 14) Morichika K, Hashimoto T, Kusano M, et al: Association 467-476. (in Japanese) of obesity with reflux esophagitis. Juntendo Medical 29) Hatafuku T, Watanabe M: Esophageal hiatal hernia and Journal, 2005; 51: 83-89. (in Japanese) reflux esophagitis. J Clinical Surg, 1977; 32: 1121-1129. 15) Armstrong D, Bennett JR, Blum AL, et al: The (in Japanese) endoscopic assessmentof esophagitis: a progress report 30) Ando S, Sakakibara K: Remaining stomach ligamentum on observer agreement. Gastroenterology, 1996; 111: arcuatum medianum fixation and His angle reinforce- 85-92. ment in gastric cancer operation. Operation, 1993; 47: 16) Lundell LR, DentJ, BennettJR, et al: Endoscopic 95-100. (in Japanese) assessment of oesophagitis: clinical and functional 31) The Japanese Society of Gastrointestinal Cancer Screen- correlates and further validation of the Los Angeles ing: Annual Report of Gastrointestinal Cancer Screen- classification. Gut, 1999; 45: 172-180. ing. J Gastrointestinal Cancer Screen, 2014; 52: 70-96. 17) Stomach X-Ray Radiography Standards Committee: (in Japanese) Final Draft Report: New standards for stomach X-ray 32) Sekiguchi T, Oowada T, Hagihara O, Kimura M: radiography (indirect and direct). Jpn J Gastroenterol Prevalence of reflux esophagitis in 2000. Nihon Rinsho Mass Survey, 2002; 40: 437-447. (in Japanese) Naikaikai Zassi, 2005; 20: 393-402. (in Japanese) 18) Youden WJ: Index for rating diagnostic tests. Cancer, 33) Nagoshi A, Kusano M, Harasawa S: Epidemiology and 1950; 3: 32-35. pathogenesis of reflux esophagitis. Clin Gastroenterol, 19) Carlsson R, DentJ, Bolling-SternevaldE, et al: The 2007; 10: 431-435. (in Japanese)

113