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Keywords:

  • Barrett;
  • gastro-oesophageal reflux;
  • impedance monitoring;
  • oesophagitis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References

Abstract  The aim of the study is to compare the characteristics of reflux episodes in controls and in patients with various degrees of oesophagitis and Barrett’s oesophagus. Ambulatory 24-h impedance-pH tracings were analysed from healthy volunteers, patients with non-erosive reflux disease (NERD), patients with grade A oesophagitis, grade B oesophagitis, grade C or D oesophagitis and patients with a short segment (<2 cm) of Barrett’s metaplasia. The number of acid and weakly acidic reflux episodes increased from 25.9 ± 3.9 to 17.9 ± 1.5 in the controls, 39.9 ± 6.3 to 33.4 ± 5.7 in the patients with NERD, 46.6 ± 6.2 to 40.4 ± 9.2 in grade A, 68.2 ± 9.2 to 49.2 ± 12.3 in grade B, 79.8 ± 15.6 to 47.4 ± 4.6 in grade C/D and 75.1 ± 7.9 to 37.3 ± 8.5 in the patients with Barrett. The proportion of reflux episodes that is acidic or alkaline was similar all groups. Comparison with normal values revealed that none of the controls, 40% of the patients with NERD, 50% of the patients with grade A, 80% of the patients with grade B and all patients with grade C/D or Barrett’s oesophagus had an abnormally high total number of reflux episodes. In the patients with severe oesophagitis a significantly higher percentage of reflux episodes reached the proximal oesophagus (43.8%) compared to the patients with Barrett’s oesophagus (19.2%). With increasing degrees of oesophagitis, patients have more reflux episodes but a large overlap between the groups exists making comparison with normal values of limited relevance. In patients with Barrett’s oesophagus fewer reflux episodes reach the proximal oesophagus which might explain their low sensitivity to reflux.


Abbreviations:
GORD

gastro-oesophageal reflux disease

LOS

lower oesophageal sphincter

NERD

non-erosive reflux disease

PPI

proton pump inhibitor

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References

The majority of patients who present with symptoms suggestive for gastro-oesophageal reflux disease (GORD) do not have mucosal damage, as observed during upper endoscopy. Either these patients do not have reflux disease, already use acid suppressive medications that healed previous erosions or simply never have developed oesophagitis. Thus, only a minority of the patients with reflux symptoms presents with erosive oesophagitis or Barrett’s oesophagus. Patients with erosive oesophagitis and Barrett’s oesophagus have a higher oesophageal acid exposure, compared to patients with non-erosive reflux disease (NERD) and healthy controls.1–5 While patients with mucosal lesions have a higher oesophageal acid exposure, it is not known whether their reflux patterns differ only in quantity of acid exposure or differences exist in composition, proximal extent and volume of the reflux episodes. It has been suggested that patients with more severe reflux disease have relatively more acid reflux compared to healthy subjects, suggesting differences in gastric acid distribution, but this could not be confirmed by others.6,7

Various publications have shown that the proximal extent of reflux episodes is an important determinant of whether or not a reflux episode is perceived.8,9 It has been suggested that a relatively high proportion of proximally extending reflux episodes causes the high sensitivity to reflux in patients with a relatively low acid exposure and that reduction of the proximal extent of reflux episodes subsequently results in a reduction of reflux symptoms.10,11 On the other hand, it could be suggested that patients with Barrett’s oesophagus have a relatively high proportion of short segment reflux episodes explaining why these subjects have metaplasia only in the most distal oesophagus, and why they are often relatively insensitive to gastro-oesophageal reflux.12 While the differences in reflux patterns are thus certainly important and potentially have clinical implications, they are not studied well and comparative data between various degrees of reflux disease are lacking. We hypothesise that patients with Barrett’s oesophagus have both quantitatively and qualitatively different reflux profile compared to the other groups, which in part would explain their paradoxically low sensitivity to acid reflux.

The aim of this study was therefore to compare the characteristics of acid, weakly acidic and weakly alkaline reflux episodes in controls and in patients with various degrees of oesophagitis and Barrett’s oesophagus.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References

Subjects

Oesophageal impedance-pH tracings were obtained from 10 healthy volunteers and from 50 patients with GORD. The healthy volunteers did not have a history of gastro-intestinal surgery, not did they have gastrointestinal symptoms. The patients studied were 10 consecutive patients with NERD, 10 patients with grade A oesophagitis, 10 patients with grade B oesophagitis, 10 patients with grade C or D oesophagitis and 10 patients with a short segment (<2 cm) of Barrett’s metaplasia. Patients with a longer Barrett segment were excluded as it is currently not clear whether the interpretation of impedance tracings is reliable in these subjects. The degree of oesophagitis was classified according to the Los Angeles (LA) classification.13 All patients with NERD were responsive to acid inhibitory drugs earlier, indicating that their symptoms were acid reflux-related.

All patients suffered from typical reflux symptoms (heartburn and/or regurgitation) or chest pain. Written informed consent was obtained from all subjects and the protocol was approved by the medical ethical committee of the University Medical Center, Utrecht, The Netherlands.

Study protocol

The use of gastric acid-inhibitory drugs and drugs that might influence gastrointestinal motility was discontinued at least 5 days before the measurement. Stationary oesophageal manometry was performed to determine the distance from the nostrils to lower oesophageal sphincter (LOS). Thereafter, the combined impedance-pH catheter was introduced transnasally.

Patients were instructed to consume three meals and four beverages at fixed times during the 24-h measurement period and to note these in a diary. The period spent in supine position was also noted in the diary.

Intraluminal impedance and pH monitoring

A combined pH-impedance recording system was used consisting of a pH-impedance catheter which enabled recording from six impedance segments, each recording segment being 2 cm long, and one pH sensor and a portable datalogger (Ohmega, MMS, Enschede, The Netherlands). The impedance recording segments were located at 2–4, 4–6, 8–10, 10–12, 14–16 and 16–18 cm and the pH sensor was located at 5 cm above the upper border of the manometrically localised LOS. Signals were stored in a digital system using a sample frequency of 50 Hz for impedance signals and 2 Hz for pH signals. Intraluminal pH monitoring was performed with an antimone pH electrode (Versaflex, Alpine Biomed, Fountain Valley, CA, USA).

Data analysis

In the analysis of the impedance tracings, gas reflux was defined as a rapid (>3000 Ω s−1) and pronounced retrograde moving increase in impedance in at least two consecutive impedance sites.14 Liquid reflux was defined as a fall in impedance ≥50% of baseline impedance that moved in retrograde direction in the two distal impedance sites. Mixed liquid–gas reflux was defined as gas reflux occurring during or immediately before liquid reflux. Liquid and mixed reflux episodes were classified as acidic when the pH dropped below 4; reflux episodes were classified as weakly acidic when nadir pH was between 7 and 4.15 Weakly alkaline reflux was defined as liquid or mixed reflux with a nadir pH above 7. In the analysis, the periods of meal consumption were disregarded.

Reflux episodes were considered to have reached the proximal oesophagus when they had a proximal extent of at least 15 cm above the LOS (most proximal two impedance segments). Data was compared with the normal values published by Zerbib et al.16

The temporal relationship between symptoms and reflux episodes is expressed using the symptom association probability (SAP).17

Statistical analysis and presentation of data

Comparisons between normally distributed data were performed using one-way anova followed by least significance difference (LSD) pairwise multiple comparison tests and between not normally distributed data using the Kruskal–Wallis test. Differences were considered statistically significant when ≤ 0.05. Throughout the manuscript parametric data are presented as mean ± SEM or medians.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References

Demographic data of the controls and the patients are listed in Table 1. The prevalence of a sliding hiatal hernia was 20% in the patients with NERD, 50% in both the patients with grade A oesophagitis and the patients with grade B oesophagitis, 80% in the patients with grade C or D oesophagitis and 40% in the patients with a short segment of Barrett’s epithelium. Of the patients with NERD, 50% of the patients had a positive SAP for either acid or weakly acidic reflux. The patients with LA grade A, B and C/D oesophagitis had a positive SAP in 60%, 50% and 30%. Forty percent of the patients with Barrett’s oesophagus had a positive SAP.

Table 1.    Demographics of patients and controls
 Age (years)Range (years)Male (%)
  1. NERD, non-erosive reflux disease; LA, Los Angeles classification.

Controls4223–6460
NERD4425–7240
Oesophagitis LA A4831–5850
Oesophagitis LA B5225–6250
Oesophagitis LA C/D4537–5960
Barrett’s Oesophagus4933–6160

The acid exposure time was not different between the controls and patients with NERD but increased with the more severe degrees of oesophagitis, with the patients with grade C or D oesophagitis or Barrett’s oesophagus having the highest acid exposure time, although a large overlap between the different groups exists (Fig. 1). A higher number of acid and weakly acidic reflux episodes were observed in the patients with increasing degrees of oesophagitis and Barrett’s oesophagus (Fig. 2). The proportion of total reflux episodes that was acidic and alkaline was similar in all groups and varied only little between the controls (58.4% and 1.3%), NERDs (53.9% and 0.9%), grade A oesophagitis (53.0% and 1.1%), grade B oesophagitis (57.8% and 0.5%) and grade C and D oesophagitis (62.3% and 0.7%) and Barrett’s oesophagus (66.3% and 0.7%) (Fig. 2).

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Figure 1.  Acid exposure time in controls and in patients with various degrees of reflux oesophagitis. *< 0.05 vs controls; #< 0.05 vs NERD.

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image

Figure 2.  Number of reflux episodes and proportion of total reflux episodes that is acidic, weakly acidic and weakly alkaline in controls and in patients with various degrees of reflux oesophagitis. *< 0.05 vs controls; #< 0.05 vs NERD.

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Both the number of pure liquid and the number of mixed liquid–gas reflux episodes increased with increasing severity of oesophagitis and Barrett’s oesophagus (Fig. 3). The median nadir pH reached during reflux episodes was lower in the patients with oesophagitis (LA A 3.2 ± 0.2, LA B 2.6 ± 0.1, LA C/D 2.8 ± 0.5) and Barrett’s oesophagus (2.5 ± 0.2) compared to the controls (3.8 ± 0.3) and the patients with NERD (3.6 ± 0.4) (< 0.05). The average drop in pH during reflux episodes did not differ between the different groups.

image

Figure 3.  Number of pure liquid and number of mixed liquid–gas reflux episodes in controls and in patients with various degrees of reflux oesophagitis. *< 0.05 vs controls; #< 0.05 vs NERD.

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According to the normal data of Zerbib et al. none of the controls, 40 of the patients with NERD, 50% of the patients with grade A oesophagitis, 80% of the patients with grade B oesophagitis and all patients with grade C or D oesophagitis or Barrett’s oesophagus had an abnormally high total number of reflux episodes. The percentage of subjects with an abnormal number of acid reflux and weakly acidic reflux episodes was respectively 10% and 0% in the controls, 20% and 50% in the patients with NERD, 50% and 50% in the patients with grade A oesophagitis, 80% and 70% in the patients with grade B oesophagitis, 60% and 100% in the patients with grade C/D oesophagitis and 90% and 50% in the patients with Barrett’s oesophagus.

Patients with severe oesophagitis (grade C/D) and patients with Barrett’s oesophagus had a significantly longer acid clearance time compared to the controls and the other patients (Fig. 4). The bolus clearance time was significantly longer in the patients with severe oesophagitis (grade C/D) compared to the controls and the patients with NERD, while no differences were found between the patients with Barrett’s oesophagus and the other groups (Fig. 5).

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Figure 4.  Acid clearance time of reflux episodes in controls and in patients with various degrees of reflux oesophagitis. *< 0.05 vs controls; #< 0.05 vs NERD.

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image

Figure 5.  Bolus clearance time of reflux episodes in controls and in patients with various degrees of reflux oesophagitis. *< 0.05 vs controls; #< 0.05 vs NERD.

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In the patients with severe oesophagitis (grade C/D) a significantly higher percentage of reflux episodes reached the proximal oesophagus compared to the patients with Barrett’s oesophagus, while no differences were found between the other groups (Fig. 6).

image

Figure 6.  Proportion of reflux episodes reaching the proximal oesophagus in controls and in patients with various degrees of reflux oesophagitis.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References

This study confirms earlier findings that with increasing severity of mucosal damage there is an increase in the oesophageal acid exposure. A novel finding is that, not only the number of acid reflux episodes but also the number of weakly acidic reflux episodes is increased in patients with severe oesophagitis and Barrett’s oesophagus. The failure of the antireflux barrier that causes GORD is not selective for either acidic or weakly reflux, as both reflux episodes are increased in the patients with GORD and the proportion between the two types of reflux episodes is similar in all groups. A gradual increase in pure liquid and mixed liquid–gas reflux episodes was found in the patients with increasing degrees of oesophagitis. The acid exposure time of the patients with short-segment Barrett’s oesophagus is comparable to the patients with more severe oesophagitis. It is important to realise however, that the overlap in acid exposure time and number of reflux episodes between the different groups is large, and that acid exposure time and number of reflux episodes are related to mucosal damage but do not predict this reliably. The sometimes observed discrepancy between severity of acid exposure and mucosal damage can be explained by the fact that mucosal damage is not only dependent on number and pH of reflux episodes but also on the mucosal resistance and the presence of bile acids and pepsin in the refluxate.18 Besides an increasing number of reflux episodes also the duration of reflux episodes and the proximal extent of the reflux episodes were larger in the patients with increasing degrees of oesophagitis. Longer acid and bolus clearance times suggest higher volumes of reflux and an impaired clearance of refluxate.19

As acid exposure is related but does not predict mucosal damage, it cannot be used to diagnose GORD as for the diagnosis of GORD either mucosal damage of symptoms related to reflux need to be present. A high acid exposure neither predicts oesophagitis, nor proves that symptoms are related to reflux. On the other hand, a very high acid exposure time was only found in those with oesophagitis and Barrett. Comparison with normal values revealed that between 40% and 100% of the patients had an abnormally high number of total reflux episodes, while between 20% and 90% of the patients had an abnormally high number of acid reflux episodes and between 50% and 100% of the patients had an abnormally high number of weakly acidic reflux episodes. This implies that, when using a certain number of reflux episodes as a cut-off to diagnose GORD, many patients will be missed and a low sensitivity will result. We therefore argue that comparing the number of reflux episodes, either acid or weakly acidic, with normal values is of limited value in the clinical workup of a patient with reflux symptoms.

The number and duration of acidic and weakly acidic reflux episodes increased with increasing severity of oesophagitis and the reflux pattern found in the patients with Barrett’s oesophagus differed only in proximal extent from the patterns found in the other groups. Earlier studies have shown that reflux episodes reaching the proximal oesophagus are important in triggering symptoms, and perhaps the limited number of proximal reflux episodes in the patients with Barrett’s oesophagus can, in part, explain why patients with Barrett’s oesophagus often report relatively few symptoms.8 Furthermore, the high acid exposure just above the squamocolumnar junction can explain why the patients all have only a short segment of intestinal metaplasia. While in most studies patients with Barrett’s oesophagus have a higher oesophageal acid exposure compared to patients with severe oesophagitis, this was not the case in our study.18,20 This can also be explained by the fact that we only included patients with a short segment Barrett’s epithelium, while the degree of oesophageal acid exposure is related to the length of the Barrett segment, and in other studies patients usually had longer Barrett segments.4 Recently, it has been shown that experimentally-induced oesophagitis leads to more proximally extending reflux episodes.21 In our study, a trend towards an increased proximal extent of reflux episodes was observed with increasing severity of oesophagitis but this did not reach significance. Furthermore, the proximal extent of patients with NERD was not significantly higher than the extent of reflux episodes of the healthy controls, which is apparently in contrast to an earlier study of our group.9 However, in that study the patients with an increased proximal extent were all SAP positive, while this is not the case in the patients with NERD in the current study.

Although it has often been suggested that duodenogastro-oesophageal reflux plays an important role in the pathogenesis of Barrett’s oesophagus, patients with Barrett oesophagus did not have a higher proportion of weakly alkaline reflux episodes. Firstly, this seems paradoxical, however weakly alkaline reflux is not synonymous to duodenogastro-oesophageal or bile reflux. In a normal anatomic situation bile has to pass the stomach before it can enter the oesophagus. A relatively low volume of bile is mixed intra-gastrically with a large volume of acidic juice before it can enter the oesophagus. Therefore, bile reflux is probably most often acidic. The finding of a low number of alkaline reflux episodes thus does not exclude bile as a causative agent in the pathogenesis of Barrett metaplasia.

In summary, this study shows that with increasing degrees of oesophagitis patients have more and longer acid and weakly acidic reflux episodes, while weakly alkaline reflux episodes are rare in all groups. While the mean values of acid and weakly acidic reflux episodes are very different between the different patients groups and are related to severity of mucosal damage, a large overlap exists. We conclude that the large overlap in isolated parameters such as number of reflux episodes or acid exposure between the various groups implies that comparison with normal values is only of limited relevance and cannot be used to diagnose reflux disease. In patients with Barrett’s oesophagus only little reflux episodes reach the proximal oesophagus which can in part explain why these subjects have a low sensitivity for gastro-oesophageal reflux.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References