Is Mucosal sensitivity a reliable predictor o f disease severity?
5.3 Patients and Methods,
A prospective study group o f 10 asymptomatic control patients, 22 patients with Barrett’s CLO and 43 patients with varying grades o f endoscopic oesophagitis was used to assess mucosal sensitivity (Table 4.1).
The controls were volunteers, the B arrett’s CLO patients were undergoing endoscopic surveillance and were already part o f the B arrett’s register. The majority o f the GORD patients were recently diagnosed. All trial patients had symptomatic reflux and were on acid suppression therapy.
Each patient was asked to refrain from solids and liquids for 6 hours. Each underwent perfusion of their recognised endoscopic abnormality, following the placement of a fine bore nasogastric tube with 3 different solutions o f 30 ml O.IM hydrochloric acid, 30 mJ 0.1 M sodium bicarbonate and 30 ml normal saline. The tip o f the fine bore tube was placed 5. 0 cm proximal to the recognised endoscopic abnormality.
The patients were unaware o f the composition o f the solutions and were asked if the infusion of the above solutions induced heartburn and if so, to grade it on a scale o f 0 for asymptomatic patients, 1 for mild symptoms, 2 for moderate and 3 for severe symptoms. In addition, the onset o f symptoms were noted and calculated with a score of 0 if asymptomatic, 1 for immediate, 2 for intermediate and 3 for late onset heartburn. All patients within the 2 trial groups had prior endoscopy and their diagnosis was histologically based.
H2 receptor antagonists and proton pump inhibitors were discontinued for a minimum of 5 or 7 days respectively prior to the investigations. Any patient that was undergoing simultaneous investigation for ischaemic heart disease, or had a systemic disorder which resulted in marked LOS dysfunction, such as scleroderma or any other alternative foregut pathology such as the presence o f H. pylori or peptic ulcer disease was excluded from this study. In order to obtain a homogenous patient study group, all patients with short segment Barrett’s CLO and patients with grade IV changes (Savary Millar) were also excluded. In total 2 patients with B arrett’s CLO and 5 with GORD were excluded from the study.
Statistical analysis.
The Wilcoxon signed rank test was used in the analysis o f the validation data. The Kruskal Wallis one way analysis o f variance (ANOVA) for the comparison of more than two independent group medians was used. Dunn’s multiple comparison test was subsequently used for the comparison o f two independent group medians, where p < 0.05 was considered significant.
5.4 Results.
Patient demographics.
10 asymptomatic control patients (median age 40, 5 males, 5 females), (20 / 22) patients with Barrett’s CLO (median age 64,14 males, 8 females no evidence o f high grade dysplastic changes, 2 patients with short segment Barrettt’s CLO) and (38 / 43) patients
with varying grades of endoscopic oesophagitis (median age 51, 22 males, 18 females, 3 patients with grade IV Savary Millar changes, the remainder had grade I - 1 1 changes) was undertaken.
Table 5.1 Validation data Symptom score Day 1
Onset Symptom score Day 2 Onset 0.9 % saline 0 (- 0.04 - 0.64) 0.0 (-0.1 - 0.9) 0 (- 0 .1 0 -0 .5 0 ) 0.0(-0.3- 1.3) 0.1 M H C L 2 .0 (1 .6 4 -2 .7 6 ) 1.0 ( 0 .8 - 1 .3 ) 2.0 (1.57 -2.63) 1 .0 (0 .9 -1 .5 ) O.IM H C 03 1.0(0.52 - 1.48) 2,0 (0.8 - 2.3) 1.0 (0 .4 9 -1 .3 1 2.0(0.9 - 2.3) Water
Symptom severity and onset
The majority o f patients were asymptomatic on both days. No significant difference was demonstrated between the median symptom scores and onset values obtained, on either day.
Acid
Symptom severity
Increased median values were obtained on day 1, 2.0 (95 per cent c.i.1.64 — 2.76). and day 2, 2.0 (95 per cent c.i.1.57 - 2.63), on acid perfusion in comparison to the other samples. No significant difference was demonstrated between the median scores obtained, for acid perfusion, on either day.
Symptom onset
A reduction in symptom onset times was obtained, as anticipated, following acid perfusion in comparison to saline and alkaline perfusion.
Base
Symptom severity
Increased median values were obtained on day 1, I.O (95 per cent c.i.0.52 - 1.48) and day 2, 1.0 (95 per cent c.i.0.49 - 1.31), on alkaline perfusion on comparison to perfusion with normal saline alone. No significant difference was demonstrated between the median scores obtained, for alkaline perfusion on either day.
Symptom onset
Median symptom onset times, were increased on alkaline perfusion on comparison to acid and normal saline.
Table 5.2 Median values for symptom score and onset
Control GORD Barrett’s
0,9 % saline score 0.0 (-0.10 - 0.50) 0.0 (-0.01 - 0.17) 0.0 (-0.05 - 0.15) Onset time 0.0 (- 0.27 - 1.27) 0.0 (- 0.03 - 0.45) 0.0 ( -0.11 - 0.31) 0.1 M HCL score 2.50 (2.12-2.88) 2.0 (1.62- 2.22) 0.0 (0.14 - 0.85) Onset time 1.0 (0 .8 7 - 1.33) 2.0 ( 1 .4 6 - 1.96) 0.0 (0.31 - 1.58) 0. 1 M H C 03 1.5 (0.56-2.24) 0.0 (0.36 - 0.90) 0.0 (- 0.8 - 0.38) Onset time 1.0 ( 0.41 - 1.58) 0.0 (0.65 - 1.45) 0.0 ( - 0.12 - 0.62) W ater
Symptom severity and onset
The majority o f patients were asymptomatic in all patient groups, in view o f this no significant difference was observed in median symptom scores or onset times, between the patient groups.
Acid
Symptom severity.
A reduction in median symptom scores (and thus mucosal sensitivity) were experienced in the Barrett’s CLO group 0.0 (95 per cent c.i. 0.14 - 0.85) in comparison to the GORD 2.0 (95 per cent c.i. 1.62 - 2.22) and the asymptomatic control groups 2.5 ( 95 per cent c.i. 2.12 - 2.88) (Fig. 5.2).
The reduction in mucosal sensitivity for the B arrett’s CLO patient group was statistically significant in comparison to the GORD (p < 0.001) and the asymptomatic control groups (p < 0.001), using a combination of ANOVA (Kruskal Wallis) and D unn’s multiple comparison test.
Symptom onset
Median symptom onset times were increased in GORD 2.0 (95 per cent c.i. 1.46 - 1.96) in comparison to the control group 1.0 (95 per cent c.i. 0.87 - 1.33). A large number o f B arrett’s patients were asymptomatic 0.0 ( 95 per cent c.i. 0.31 - 1.58) (Fig. 5.5).
The reduction in symptom onset time for the B arrett’s CLO patient group was statistically significant in comparison to the GORD patient group alone (p < 0.05), using a combination of ANOVA (Kruskal Wallis) and D unn’s multiple comparison test.
Base
Symptom severity.
A reduction in median symptom scores were experienced in the Barrett’s CLO patient group 0.0 (95 per cent c.i. -0.80 - 0.38 ) in comparison to the asymptomatic control group 1.5 (95 per cent c.i. 0.56 - 2.24). There was little difference with the GORD patient group 0.0 (0.36 - 0.90) (Fig 5.3).
The reduction in mucosal sensitivity between the B arrett’s CLO and the asymptomatic patient group was statistically significant (p < 0.01), using a combination o f ANOVA (Kruskal Wallis) and Dunn’s multiple comparison test.
Symptom onset.
Median symptom onset times were increased in the control patient group 1.0 (95 per cent c.i. 0.41 - 1.58) in comparison to the GORD 0.0 (95 per cent c.i. 0.65 - 1.45) and B arrett’s patient groups 0.0 ( 95 per cent c.i. - 0.11 - 0.62) (Fig. 5.6).
The reduction in symptom onset time for the B arrett’s CLO patient group was statistically significant in comparison to the GORD patient group alone (p < 0.05), using a combination o f ANOVA (Kruskal Wallis) and Dunn’s multiple comparison test.
5.5 Discussion.
This study suggests that mucosal sensitivity in patients with Barrett’s CLO is reduced both to acid and alkaline perfusion, in comparison to an asymptomatic control group (Table 5.2) and to acid perfusion alone on comparison to a GORD patient group.
It is assumed that the long standing duration o f the refluxate produces a reduction in mucosal sensitivity, due to down regulation o f the sensory receptors, which may explain why a significant number of patients with B arrett’s CLO present de novo with an associated complication, such as malignancy. This is well establised for acid reflux, but the relationship between mucosal sensitivity and alkaline reflux is intriguing. The implication o f alkaline reflux in the recognised sequelae o f GORD and B arrett’s CLO, would suggest that patients that have documented prolonged exposure o f alkaline
contents in their refluxate, would also have a reduction in mucosal sensitivity, placing them at risk o f further sequelae, in a manner similar to acid reflux.
The validation data reveals increased median symptom scores following acid perfusion in comparison to alkaline perfusion and normal saline (Table 5.1). A large proportion o f patients were asymptomatic to saline perâision. Symptom onset arose over the shortest time period following acid perfusion. Using the Wilcoxon Rank test no significant difference was obtained between repeat median mucosal sensitivity scores or onset measurements, obtained on separate days.
As anticipated, there was a global reduction in mucosal sensitivity to acid perfusion in the B arrett’s CLO group in comparison to the GORD (p < 0.001) and control groups (p < 0.001) respectively (Fig. 5.2). The results obtained are similar to Bernstein’s original work and more recently Ball and W atson’s work from 1988 and thus provides a reliable and further effective means o f validating data from the present study.
A reduction in mucosal sensitivity was observed with alkaline perfusion, on comparison o f B arrett’s CLO with the asymptomatic control group (p < 0.01), but no difference was noted between the Barrett’s CLO and the GORD patient groups (Fig. 5.3).
Overall reduced symptom scores were experienced with alkaline perfusion. This may have arisen due to the mechanism o f mucosal injury. Alkaline reflux exerts a lesser injury on the mucosa through a denaturing process, which involves lipid solubilisation, where as acid induces an oesophageal burn.
Prior sensitization o f the mucosa ie the degree o f mucosal injury produced by the acid infusion may have been so severe, that any symptoms produced by alkaline perfusion were negated by the initial injury.
Our model is hypothetical and the mechanism o f duodeno GORD, whereby contents from the duodenum are refluxed into the distal oesophagus have not been reproduced. If we were to extend our results further to a clinical setting, it could be implied that due to the increased distance that alkaline components have to travel, there may be an increased dilutional effect, resulting in reduced bile acid delivery to the distal oesophageal mucosal receptors.
Other factors which may be o f relevance are the sensory receptors located within the oesophageal mucosa. It has been suggested that they have an increased threshhold for hydrogen ion sensitivity in comparison to bile acids and their salts and the distribution o f alkaline specific receptors in the distal oesophagus may be reduced in number (Scarpignato, personal communication 2000). The lack o f mucosal sensitivity to water, is
interesting (Fig 5.1). GORD patients may experience severe odynophagia and thus one would expect some symptoms to be experienced within the GORD subset. Increased symptom severity may have been experienced if the temperature had been varied and the water used was not at room temperature.
Symptom onset was increased in the B arrett’s CLO patient group in comparison to the GORD (p < 0.05) and the control groups respectively, for both acid and alkaline perfusion. In view o f the longstanding nature and duration o f symptoms associated with B arrett’s CLO, this was anticipated. The rationale for this may be closely linked to the same reason as to why these patients also had reduced symptom scores.
The absence o f H pylori in all patient categories, would suggest that the symptoms experienced reflect true mucosal sensitivity. Placement o f the fine bore tube in the distal oesophagus, proximal to the recognised endoscopic abnormality, would suggest that even in the presence o f H pylori, there should be little difference in the results obtained. The significance o f using sodium bicarbonate as opposed to using commercial bile preparations may be relevant. The latter may induce a more pronounced oesophageal injury, creating an increase in mucosal sensitivity. A direct comparison is indicated in further studies.