What is a Normal Esophagogastric Junction?

Vol. 62, No.4 Printed in U.S.A.

GASTROENTEROLOGY

Copyright © 1972 by The Williams & Wilkins Co.

WHAT IS A NORMAL ESOPHAGOGASTRIC JUNCTION? B. VENKATACHALAM, M.D., L. R. DA COSTA, M.B., M R.C.P., . M.D., S . K. L. Ip, M.D., D.M.R., AND I. T . BECK, M.D., PH.D., F R . .C.P. (C), F.A.C.P.

Division of Gastroenterology and the Departments of Medicine and Radiology, Hotel Dieu Hospital, and the Department of Medicine and the Department of Physiology, Queen's University, Kingston, Ontario, Canada

This study deals with the incidence of apparent abnQrmality of the esophagogastric junction in a group of young asymptomatic individuals. We have defined the esophagogastric junction to be normal if the following criteria were met: (1) absence of hiatus hernia by X-ray; (2) absence of significant gastroesophageal reflux measured by intraesophageal pH electrode; (3) normal pressure characteristics of the lower esophageal sphincter; and (4) normal location of the mucosal esophagogastric junction as measured by transmural potential difference studies. Sixty volunteers (30 male and 30 female) with no upper gastrointestinal complaints were studied. Their ages ranged from 20 to 35 years. Results indicate that, out of 60 individuals Xrayed, 22 had hiatus hernia. Of the remaining 38 who did not have a hiatus hernia, significant gastroesophageal reflux was found in 7. Four subjects studied by X-ray and by intraesophageal pH electrode did not undergo further studies. Of the remaining 27 subjects, 5 had gastroesophageal sphincters which were abnormal. A further 4 had abnormal potential difference transition zones at the esophagogastric junction. Accordingly, of the 60 asymptomatic young subjects, 38 (63%) had at least one abnormal test of the four parameters measured at the esophagogastric junction. With this high incidence of "abnormality" in young asymptomatic subjects, the validity of the accepted definition of normalcy at the gastroesophageal junction is questioned. Although it is impossible to predict whether some of the subjects who had abnormal tests will develop symptoms of esophagitis in the future, it is important to caution against overinterpretation of any of these individual tests in clinical situations. It is generally accepted that a normally functioning esophagogastric junction can be differentiated from an abnormal one by X-ray examination, 1 intraesophageal pH measurement,2 intrasphincteric pressure studies,3 and investigation of junctional potential difference (PD) changes. 4 Each Received July 13, 1971. Accepted November 26, 1971. Address reprint requests to: Dr. I. T. Beck, Division of Gastroenterology, Hotel Dieu Hospital Kingston, Ontario, Canada. Supported by Grant no. 223 of the Ontario Cancer Treatment and Research Foundation.

of these methods may demonstrate abnormalities in apparently healthy individuals. Approximately 33% of patients who have no gastrointestinal symptoms have hiatus hernias. 5 Reflux was also demonstrated by intraesophageal pH studies in asymptomatic individuals. 6 , 7 Ineffective sphincter pressure was shown to be present in small proportion of apparently healthy people who had no reflux. 8 To our best knowledge, no one has quantitated the total incidence of abnormality at the esophagogastric junction in asymptomatic young people by using all of the above-mentioned methods. 521

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During the course of another study in which some physiological aspects of the normal esophageal sphincter were to be investigated, it was necessary to accumulate a number of healthy young individuals (volunteers) who had "normal" esophagogastric junctions. In order to be included in the study, the volunteers had to fulfill the following criteria: (a) absence of any upper gastrointestinal symptoms; (b) ages between 20 and 35 years; (c) absence of hiatus hernia by X-ray; (d) absence of significant gastroesophageal reflux measured by intraesophageal pH electrode; (e) normal pressure characteristics of the lower esophageal sphincter; and (£) normal location of the mucosal esophagogastric junction as measured by transmural PD studies. We soon became impressed by the number of apparently healthy asymptomatic young volunteers who had to be excluded from the study because they were unable to meet one or more of these criteria. This report deals with the cumulative data of the process of exclusion due to "abnormal" esophagogastric junction, and serves to assess the incidence of apparent abnormality of the esophagogastric junction in a group of young asymptomatic subjects.

Materials and Methods Clinical subjects. Sixty (30 male and 30 female) healthy asymptomatic university and nursing students and house staff between the ages of 20 and 35 served as subjects. Prior to inclusion in the study, the subjects were requested to answer a standard questionnaire which included questions related to the absence of epigastric pain, heartburn, dysphagia, chest pain, nausea, and vomiting. The subjects were una ware of the reason for the questions and of the criteria for inclusion into the study. Four subjects had to be excluded somewhere along the investigation: 1 left town, 1 became pregnant, and 2 were unable to cooperate during the esophageal pressure studies. X-ray investigation was performed by the method of Wolf and Guglielmo,' in the prone 'position using a bolster. All fluoroscopic examinations were performed by the same radioologist but the films were reviewed by two radiologists independently. A hiatus hernia

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was considered to be present if at least two of the three criteria described below were found to be present by both radiologists. The criteria considered were (a) the presence of a mucosal ring or a notch above the level of the hiatus, (b) the presence of a supradiaphragmatic pouch which did not participate in esophageal peristalsis and which was not in direct line with the body of the esophagus, and (c) the presence of gastric folds in the suprahiatal segment. A widening of the hiatus alone was not considered to be a sign of hiatus hernia. In addition, the presence or absence of reflux during fluoroscopy was also noted. Gastroesophageal reflux was studied by measuring intraesophageal pH as described by Tuttle et al. 2 except that the stomach did not contain extra saline and acid since an esophagea1 acid perfusion test was not done prior to the reflux test. The pH electrode was attached to a single noninfused pressure sensor catheter to detect whether the bulb of the electrode (Beckman-39042) was in the stomach, the sphincter, or the esophagus. The electrode was first introduced into the stomach to ascertain that the gastric pH was acid. After this the electrode was withdrawn into the esophagus and placed 5 cm above the lower esophageal high pressure zone for approximately 20 min. During this period of time, each subject was studied in the supine, supine with legs elevated, prone, right, and left lateral decubitus, both while lying horizontally and in the Trendelenburg position. In all these positions the subject was studied both without and during manual abdominal massage. In addition, the esophageal pH was also investigated while the subject was standing and stooping forward. Abnormal reflux was considered to be present if, during any of these maneuvers, the intraesophageal pH fell below 4 and did not return to neutral within 30 sec. The changes in pH at the level of the electrode were measured by using a Beckman Zeromatic II pH meter (Beckman Instruments, Inc., Scientific and Process Instruments Division, Fullerton, Calif.), and were recorded on a Beckman type R Dynograph (Beckman Instruments, Inc.). Esophageal sphincter pressures and transmural potential difference measurements were performed simultaneously. Esophageal pressure studies were carried out with a constant infusion method essentially similar to that described by Winans and Harris,3 except that Ringer's solution (0.382 ml per min) was used as the infusion solution. The measuring catheters used for this study were joined in a fourlumen catheter bundle (U. S. Catheter and In-

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strument Corp., Glens Falls, N. Y. Project no. 68-038). Each catheter had a 1.6-mm internal diameter and the bundle had an over-all outside diameter of approximately 6 mm. Each of the three pressure catheters had a 2-mm side opening and these were arranged 4 cm apart. The fourth catheter was used for measurement of transmural potential difference between mucosa and scarified skin, as described by Hernandez and Beck,9 using Beckman 40249 (silver-silver chloride electrodes) immersed in Ringer's solution. These electrodes were connected to the input of a Beckman Expandomatic pH meter (Beckman Instruments, Inc.) which was used as a voltmeter. The output of this instrument was transmitted to one of the channels of the Beckman type R Dynograph. The orifice of the PD sensor catheter was at the same level as the middle pressure sensor catheter. All four orifices of the fused catheter bundle were introduced into the stomach and then were withdrawn at V2-cm intervals through the sphincter into the body of the esophagus. The pressures were measured with Statham transducers (Statham Laboratories, Inc., Los Angeles, Calif.) and recorded on three channels (leads) of the type R Dynograph. The analogue data so obtained were converted to digital data by two investigators independently, and the pressure gradient between gastric and the highest pressure in the lower high pressure zone was calculated, both in inspiration and expiration. The length and the location of the transition zone from gastric PD to esophageal PD were also assessed. The sphincter pressure was considered abnormal if there was no gradient between gastric and sphincteric pressure in expiration (hypotensive sphincter) in neither of the leads, or if the gastro-sphincteric expiratory pressure gradient was equal to, or more than 30 mm Hg (hypertensive sphincter) in all three leads. The mucosal junction from gastric to esophageal mucosa was considered abnormal if the PD transition occurred above (proximal to) the level of the simultaneously measured high pressure zone, or if the PD transition exceeded 5 cm in length. 10 Order of screening was as follows: all the volunteers underwent a radiological study. Those who had hiatus hernias or radiological demonstrable reflux were excluded from further investigation. If the X-ray was normal, intra esophageal pH was studied. Any subject demonstrating reflux by this test was excluded from further studies. The remaining subjects with normal X-rays and normal intraesophageal pH underwent simultaneous gastroesopha-

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geal pressure and transmural potential difference measurements.

Results Radiological diagnosis of hiatus hernia was based on the presence of at least two of the criteria described in the section on methods. There were 22 subjects in whom this diagnosis was made. In 20 of 22 subjects all three criteria were noted by both radiologists. In 1 subject, two of the necessary criteria were seen by oile radiologist, and all three by the other. In a 2nd subject, only two of the criteria were reported to be present by both radiologists. There were 38 subjects who were considered to have no hiatus hernia. In the Xcrays of 3 of these, one radiologist observed one of the criteria described for hiatus hernia, and, in an additional 2, both radiologists noted a single criterion. The presence or absence of radiologically demonstrable reflux was based on the fluoroscopic observation of one radiologist. Gastroesophageal acid reflux occurred in 'Z asymptomatic subjects who did not fulfill the criteria of having a hiatus hernia. In 4, this reflux occurred in the right lateral position, in 2 while bending forward, and in 1·during abdominal massage in the Trendelenburg position. The gastroesophageal sphincter pressure gradient in 3 out of 27 subjects was 0 mm Hg in expiration and in 2 subjects it was over 30 mm Hg in expiration (31 and 34 respectively). In addition, these latter 2 subjects, although they had no symptoms, had multiple tertiary contractions in the body of their esophagus, and fulfilled the criteria for the diagnosis of diffuse esophageal spasm. The transition zone of the transmural potential difference in 3 subjects was 6V2, 6 1/2 , and 7 cm respectively. In 1 of the subjects, it occurred 3 cm above the proximal end of the high pressure zone. The cumulative data in table 1 indicate that at least 63% of all normal asymptomatic volunteers had some abnormality of their esophagogastric junction if tested as described. Four out of 60 subjects were tested by only two tests and did not un-

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VENKATACHALAM ET AL. TABLE

Test to demonstrate abnorm ality

X-ray Intraesophageal pH Pressure study of sphincter

Transmural PD·

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1. Cumulative data

Type of abnormality

Total no. of subjects tested

Hiatus hernia Without reflux With reflux Acid reflux Hypotensive sphincter Hypertensive sphincter (with diffuse spasm in body of esophagus) Abnormal transition zone

N o. of subjects with ahnor· mal test

60 1!}22 38 27

22

7 0

Percentage abnormal

Cumulative percentage of abnormality

3~:}37%

~~:}37%

18%

;} 5

1~:}18%

4

18%

48%

~;:}57%

63%

Four subjects who were studied by X-ray and intraesophageal pH did not undergo further studies. • PD, potential difference.

o

dergo pressure and PD studies. The 63% cumulative abnormality was calculated assuming that all 4 would have had normal sphincter pressures and normal PD. The table indicates that 9 out of 27 (33%) of normal individuals had abnormal pressure or PD studies. Accordingly, it would be justified to assume that at least 1 of the 4 subjects not tested would have had either an abnormal sphincter pressure or an abnormal PD. If this is taken into consideration, 65% of the subjects would have had at least one abnormal finding at their esophagogastric junction. If the 4 subjects who did not have the full series of tests were excluded from the calculation entirely; i.e., if the total group was considered to be 56 and not 60, the cumulative abnormality would be 69%.

Discussion A 63% incidence of abnormality at the esophagogastric junction in normal asymptomatic individuals seems at first surprising. A review of the literature, however, indicates that a certain percentage of abnormality, demonstrated by each of the tests used, was sporadically reported in the past in asym'p tomatic normal individuals. Dyer and Pridie 5 report a 33% incidence of hiatus hernia by X-ray in asymptomatic patients. Our subjects were all young, and one would expect a lower incidence in this group. Dyer and Pridie,5 however, point out that the incidence of hiatus hernia in their study, in the subjects who were below the age of 30 years,

was similar (30%) to that of the entire series. The 37% incidence of hiatus hernia shown in our group is in agreement with their data. The incidence of gastroesophageal reflux measured by pH electrode in the lower esophagus in normal individuals depends on the method and criteria used. Short bursts of reflux can be observed in normal individuals during gaseous eructation, but, in these subjects, the esophageal pH returns to normal owing to rapid clearing of the regurgitated acid. l1 We considered the fall of pH to be abnormal if it lasted more than 30 sec. Kantrowitz et al. 7 demonstrated that 8 out of 17 of their controls (subjects who had no hiatus hernia and no symptoms of reflux) had minimal, but two (12%) had moderate, reflux. Our 18% incidence of reflux is in the same range. In addition, Haddad,6 while correlating gastroesophageal reflux and sphincter pressures, found that of the 11 patients who had reflux but had no hiatus hernia, 2 had no symptoms. It is interesting to note that Cohen and Harris 12 indicate that hiatus hernia alone does not predispose to reflux. In our series radiological reflux was found only in those subjects who also had a hiatus hernia. If one assumes, however, that the acid reflux demonstrated by intraesophageal pH electrodes has the same significance as the reflux of barium during radiological examination, the findings of Cohen and Harris 12 are supported by our results, too. In this study, the incidence of reflux as demonstrated by X-ray was 4 out

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of 22 (18%) in subjects who had a hiatus hernia, and the incidence of reflux demonstrated by pH electrode was 7 out of 38 (18%) in subjects who did not have a hernia. Low gastroesophageal pressure gradient was found by us in three out of 27 asymptomatic volunteers (11 %). The method employed to measure sphincteric pressures may influence the values obtained for the gastrosphincteric pressure gradient. Nagler and Spiro, 13 using unperfused catheters, found that 2 out of 10 (20%) of their normal subjects had gastrosphincteric pressure gradients of 2 mm Hg or less. Since they measured the highest pressure point in the sphincter, this point may have occurred during inspiration only, and, therefore, would not constitute an effective sphincter. Our data were obtained by employing a constant infusion technique similar to the method used by Pope 8 to measure yield pressures. He found that in a group of 9 control subjects who had no evidence of reflux, 2 (22%) had low sphincter pressures which were in the same range as the pressures recorded in patients with reflux. This 22% is higher than the 11% in our study. On the other hand, out of 25 asymptomatic subjects who had no hiatus hernia, Cohen and Harris, 12 using a similar technique, did not find any subjects with abnormally low sphincter pressures. In the same group they found 1 subject with a gastroesophageal sphincter gradient of 30 mm Hg. In our study there were 2 out of 27 subjects with hypertensive sphincters. Helm et al.· state that the PD transition corresponds to the gastroesophageal mucosal junction. This was confirmed by Meckeler and Ingelfinger,14 who combined PD studies with mucosal biopsies. Helm and his group· found abnormal transition zones in some normal subjects. In our study there were 4 out of 22 subjects (18%) with abnormal transition zones. A finding of such a high incidence of abo normality in one or another of the tests in normal asymptomatic subjects poses some important questions. One may ask: (a) were the test inadequately carried out; (b) were the tests or the criteria used over-

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sensitive to classify a test positive; (c) if the tests were carried out adequately and if they were not oversensitive, in view of the high incidence of abnormal findings in normal individuals, how does one define a normal esophagogastric junction, and (d) if there is such a high incidence of abnormal tests in normal individuals, what is the clinical significance of an abnormal test in a patient who has symptoms referrable to esophageal disease? All tests were performed according to established methods and ~ere evaluated by weil established and generally accepted criteria. The X-rays were read by two radiologists, and the criteria for the diagnosis of hiatus hernia were established according to a widely used clinical technique. 1 The test used for measuring reflux by intraesophageal pH electrode is also widely used. The technique employed to study lower esophageal sphincter pressure was a generally accepted method which establishes yield pressures. All tracings were read twice and the gastrosphincteric pressure gradient was determined by two investigators on every tracing. The technique to measure transmural PD was established in this laboratory, but the results obtained by this method are not dissimilar to those found using intravenous reference electrodes. 1s' 1 7 The possibility that the tests employed were oversensitive is unlikely. The radiological method described by Wolf and Guglielmo 1 uses a bolster in the prone decubitus. This is not a usual body position assumed during normal living, and it is not unreasonable to assume that hiatus hernias demonstrated in this position do not herniate during normal activity. On the other hand, it is unlikely that this maneuver would cause herniation if the anatomical basis for a hiatus hernia was not present. The method used for demonstrating reflux by pH electrode is also unlikely to be oversensitive. First, short bursts of esophageal acidity were not considered to represent reflux, and, second, the stomach was not distended by filling it with acid as was done by Kantrowitz et al. 7 The question may arise whether the

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VENKATACHALAM ET AL.

criteria for a normal lower esophageal sphincter pressure gradient were too rigid. The criterion chosen to define a low pressure sphincter can hardly be questioned since the absence of a gastroesophageal sphincter gradient in expiration indicates that, at least in this phase of breathing, the sphincter may be incompetent. The upper limit of normalcy was established based on our own normal controls, but our data are not dissimilar to those of others. IS In addition, in the 2 asymptomatic subjects in whom a "hypertensive" sphincter was found, there was also evidence of abnormal esophageal motility in the form of multiple tertiary contractions. The occurrence of diffuse esophageal spasm in asymptomatic subjects was also noted by Kramer.19 The criteria for an abnormal PD transition zone were established in this laboratory based on our own normal data. lo These criteria were subsequently reconfirmed by US,15 but these results still await support from other laboratories. If we assume that the tests were carried out correctly, according to established clinical methods, and if they are not considered oversensitive, then the finding of such a high incidence of abnormal results in a group of asymptomatic individuals poses the problem of having to define the normal esophagogastric junction. If 37% of normal subjects have a hiatus hernia, then the presence of a hiatus hernia should probably not be considered abnormal. If 11 out of 60 (18%) asymptomatic subjects have reflux demonstrated by either X-rays or by intraesophageal pH measurement, then gastroesophageal reflux is possibly not entirely abnormal. Whether this reflux will lead in the long run to esophagitis and symptoms of esophageal disease probably depends on the duration of exposure and on the inherent resistance of the esophageal mucosa. Our subjects were young and it is impossible to predict whether some of the subjects will develop symptoms of esophagitis in the future. The low incidence of hypotensive sphincter (11 %) in subjects who had no symptoms, no hiatus hernia, and no reflux does not per-

mit any other conclusion than that a low sphincter pressure does not always correlate with demonstrable reflux and, therefore, may not necessarily lead to disease. The occasional occurrence of a hypertensive sphincter (7%) accompanied by tertiary contractions in the body of the esophagus provides further evidence that diffuse esophageal spasm may not necessarily lead to the production of symptoms. 19 The significance of an abnormal PD transition zone in asymp.tomatic individuals is unknown at present, and this merits further investigation. This study does not provide an answer to the clinical significance of finding either a hiatus hernia or a gastroesophageal reflux, an abnormal lower esophageal sphincter pressure, or a PD transition zone in patients with symptoms of esophageal disease. Since any of these can be found in normal individuals, it is possible that their presence in patients with symptoms had no clinical significance. On the other hand, the development of symptoms or pathological changes depends also on the duration of exposure to an irritant and on the susceptibility of the individual esophageal mucosa to injury. It is possible that the same incompetence which causes no disease in one individual may lead to symptoms or pathological changes in a susceptible subject, and it is not impossible that some of our young asymptomatic subjects who have abnormal tests will develop esophagitis in the future. One must, however, conclude on the basis of this study that, unless the results of these tests are individually considered in the light of the clinical history and other findings in patients with esophageal disease, a positive result in any of these tests may be subject to overinterpretation. REFERENCES 1. Wolf BS, Guglielmo J : Method for roentgen

demonstration of minimal hiatal herniation. J Mount Sinai Hosp NY 23:738-741, 1956 2. Tuttle SG, Bettarello A, Grossman MI: Esopha· geal acid perfusion test and a gastroesophageal reflux test in patients with esophagitis. Gastro· enterology 38:861- 872, 1960 3. Winans es, Harris LD: Quantitation of lower

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5. 6. 7.

8.

9.

10.

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esophageal sphincter competence. Gastroenterology 52:773-778, 1967 Helm WJ, Schlegel JF, Code CF, et al: Identification of the gastroesophageal mucosal junction by transmucosal potential in healthy subjects and patients with hiatus hernia. Gastroenterology 48:25-35, 1965 Dyer NH, Pridie RB: Incidence of hiatus hernia in asymptomatic subjects. Gut 9:696- 699, 1968 Haddad JK: Relation of gastroesophageal reflux to yield sphincter pressures. Gastroenterology 58: 175-184, 1970 Kantrowitz PA, Corson JG, Fleischli DJ, et al: Measurement of gastroesophageal reflux. Gastroenterology 56:666-674, 1969 Pope II CE : A dynamic test of sphincter strength: Its application to the lower esophageal sphincter. Gastroenterology 52:779-786, 1967 Hernandez NA, Beck IT: Gastroesophageal transmural potential difference measured by a new constant infusion method. The effect of skin scarification on this potential difference. Am J Dig Dis 14:206-216, 1969 Beck IT, Hernandez NA: Transmural potential difference in patients with hiatus hernia and oesophageal ulcer. Gut 10:469-476, 1969 Vinnik IE, Kern F Jr: The effect of gastric intubation on esophageal pH. Gastroenterology 47:388-394, 1964

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12. Cohen S, Harris LD: Does hiatus hernia affect competence of the gastroesophageal sphincter? N Engl J Med 284:1053- 1056, 1971 13. Nagler R, Spiro HM: Serial esophageal motility studies in asymptomatic young subjects. Gastroenterology 41:371-379, 1961 14. Meckeler KJH, Ingelfinger FJ: Correlation of electric surface potentials, intraluminal pressures, and nature of tissue in the gastroesophageal junction of man. Gastroenterology 52:966971, 1967 15. Vidins EI, Fox JE, Beck IT: Transmural potential difference (PD) in the body of the esophagus in patients with esophagitis, Barrett's epithelium and carcinoma of the esophagus. Am J Dig Dis 16:991-999, 1971 16. Geall MG, Code CF, McIlrath DC, et al : Measurement of gastrointestinal transmural electric potential difference in man. Gut 11:3437, 1970 17. Grantham RN, Code CF, Schlegel JF: Reference electrode sites in determination of potential difference across the gastroesophageal mucosal junction. Mayo Clin Proc 45:265-274, 1970 18. Rinaldo JA, Levey JF: Correlation of several methods for recording esophageal sphincter pressures. Am J Dig Dis 13:882-890, 1968 19. Kramer P: Diffuse esophageal spasm. Mod Treat 7:1151- 1162, 1970