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Symptom evaluation in a non acidic pH range.

Non acidic reflux remains difficult to quantify. Until now it has represented the synergistic combination o f acid and bile reflux and is probably responsible for symptomatic reflux in approximately 60 % o f individuals. The concept o f reflux outside o f these conventional pH ranges, namely neutral reflux and the wide distribution o f pH ranges that some patients may experience their symptoms in, has not been addressed in the literature. Neutral reflux represents symptomatic episodes o f GOR, where the refluxate is within the neutral pH (4 - 7) range.

Thirty per cent o f GORD and thirty eight per cent o f Barrett’s CLO patients respectively, experienced the majority of their symptoms within the neutral pH range. The concept of maximal (90 %) bile and trypsin delivery to the distal oesophagus arising within the neutral pH range is well established (Vaezi et al, 1999). Bile induced oesophageal damage is dependent on the conjugation status o f the bile salts and the pH o f the distal oesophageal refluxate, with maximal mucosal damage arising when the bile salts are soluble and in a non ionised form. In a strong acidic enviroment (pH < 2) bile salts precipitate out and are thus incapable o f injury. At a pH > 7, 90 % o f bile salts are in solution but are completely ionised and are thus non toxic.

Using net acid flux as a marker o f mucosal injury, unconjugated bile salts cause maximal damage in the neutral pH range in combination with trypsin (Vaezi et al, 1999).

There is increasing evidence for the aetiological role o f neutral reflux in the initiation of junctional adenocarcinoma. An increase in villin expression ( a marker for epithelial cell

differentiation and reduced cellular proliferation) has been demonstrated, arising from the intermittent exposure o f human Barrett’s cell culture lines to a neutral pH (Fitzgerald et al, 1996). Additional evidence suggests that the intermittent exposure o f cell culture lines to bile salts, between the pH range 5 -7 increases mutation frequency with out affecting overall growth (De Meester 2000).

The validity o f patients experiencing symptomatic reflux within a neutral pH range may be contentious. These patients may primarily be alkaline refluxers and the acid responsible for the symptomatic reflux episode may subsequently be neutralised, by alkaline “bile” reflux, secondary to a significant degree o f duodeno gastro oesophageal reflux. Alternatively, it may be argued that patients experiencing their symptoms within a neutral pH range may be suffering from disorders other than GORD, such as achalasia or non ulcer dyspepsia.

Review of the physiological parameters responsible for maintenance of LOS competence, suggests that it remains difficult to reliably identify an isolated parameter which is o f sole importance and confirms that a multitude of factors are responsible for LOS integrity. The combination o f the statistical data, which confirms elevated DeMeester scores in the acid refluxers and the Barrett’s CLO patient group and the regression analysis data suggests that those patients who reflux within an acidic pH range are probably true acid refluxers. In addition this provides a reliable means o f validation and .enables effective discrimination between patients who reflux in an acidic (r = 0.68) and neutral (r = 0.02) pH range.

Thirty per cent of Barrett’s CLO patient group had a marked reduction in oesophageal motility in comparison to twenty per cent o f acid refluxers in the GORD patient group. This may suggest that an intrinsic delay in oesophageal clearance may be involved in the initiation o f both disorders, although it is o f more significance in Barrett’s CLO.

The rationale for the aggressive evaluation o f symptomatic reflux in a non acidic pH range, is increasingly justified by the knowledge that patients who experience the majority o f their symptoms within a neutral or alkaline pH range are increasingly prone to the serious sequelae o f GORD and its increased risk o f junctional gastro oesophageal adenocarcinoma. Patients who reflux in a non acidic pH range should be evaluated with a view towards consideration for anti reflux surgery, in selected cases. There is now increasing evidence supporting the prophylactic role o f anti reflux surgeiy in the preventative management of junctional malignancy (DeMeester 2000).

Mucosal sensitivity as a predictor of disease severity.

Reduced mucosal sensitivity o f the metaplastic epithelium in Barrett’s CLO, to longstanding acid reflux is well established and may explain why a significant number o f patients with Barrett’s CLO present de novo with an associated complication, such as malignancy. The implication of alkaline reflux in the recognised sequelae o f GORD and Barrett’s CLO is well established, there is however little acknowledgement in the literature about the relationship between mucosal sensitivity and alkaline reflux.

Mucosal sensitivity was markedly reduced to acid perfusion in the Barrett’s CLO group in comparison to the GORD (p < 0.001) and the asymptomatic control group

(p < 0.001) respectively (Fig 5.2). The validation data, in addition to the results obtained from the present study, 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 of

validating data from the present study. Similar results were also obtained with alkaline perfusion, on comparison of Barrett’s CLO with the control group (p < 0.01) (Fig. 5.3). No difference was noted between the B arrett’s CLO and GORD patient groups during alkaline perfusion

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 Barrett’s CLO, this was anticipated. The rationale for this may be intimately linked to the same reason as to why these patients also had reduced symptom scores.

The difference in mucosal sensitivity between acid and alkaline perfusion may have arisen due to the different physiological mechanisms by which an acid and alkaline refluxate exert their injurious effect on the mucosa. Acid functions independently of pepsin between the pH range 1 -2 and largely in synergism with pepsin between the pH range 2 - 4.5, inducing an oesophageal mucosal bum.

Alkaline injury occurs predominantly in the neutral pH range, compatible with maximal bile salt and trypsin delivery to the distal oesophagus. A denaturing process of the distal oesophageal mucosa ensues, involving lipid solubilisation which in turn opens up gap junctions to aid the intra mucosal passage o f hydrogen ions.

An alternative explanation may be that the degree o f mucosal damage produced by acid infusion is so severe, that any further symptoms produced by further alkaline infusion would be negated by the initial injury.

In a clinical setting, it could be implied that the reduction in mucosal sensitivity (and thus symptoms experienced in an alkaline pH range) may arise due to the increased distance that alkaline components have to travel. There may be an additional dilutional effect, resulting in reduced bile salt and acid delivery to the distal oesophageal mucosal receptors.

Other relevant factors may include the distal oesophageal sensory receptors having an increased threshhold for hydrogen ion sensitivity in comparison to bile acids and their salts. In addition, the distribution o f alkaline specific receptors in the distal oesophagus may be reduced in number in comparison to hydrogen ion receptors (Scarpignato 2000). The significance o f using sodium bicarbonate as opposed to using commercial bile preparations may be relevant. The latter may induce a more severe oesophageal

further studies. The use of a solution with a neutral pH and its effect on mucosal sensitivity would also be of interest, although its clinical relevance would be diminished unless there were bile acids present.

T he role of antroduodenal dysm otility.

In a small but significant minority o f patients, confirmation o f the diagnosis o f GORD remains elusive. This may be particularly so, when reflux occurs outside o f the conventional acidic pH range. In the presence o f equivocal oesophageal manometry and 24 hour pH monitoring, the choice remains between further aggressive invasive investigation through the use o f tools such as the bilitec, which analyses bilirubin content within the refluxate or empirical treatment with acid suppressants.

Non invasive assessment of antroduodenal motility, utilising electrogastrography and antral ultrasonography, in GORD is well documented and is gaining increasing acceptance, there are however no previous comparative studies with B arrett’s CLO. Antroduodenal dysmotility has been implicated in the pathogenesis o f duodenogastro oesophageal reflux, which in turn is thought to be particularly pertinent in the delivery of bile to the distal oesophagus. The role o f alkaline reflux and its implication in GORD and its sequelae Barrett’s CLO and oesophageal adenocarcinoma is well recognised.

Analysis of the present study revealed that the median pre and post prandial frequencies fell within normal limits ie slow wave activity was greater than 70 %, in all patient groups. These results were comparable to those obtained by Leahy et al (1999) and thus provide an effective means o f validation.

There was marked reduction in preprandial slow wave activity in both the Barrett’s CLO (p <0.001) and the GORD (p < 0.001)groups in comparison to the control group respectively (Fig. 6.1).There was no pre prandial difference between the B arrett’s CLO and GORD groups. Post prandial analysis confirmed a further reduction in slow wave activity in the Barrett’s CLO group (p <0.001) and a moderate increase in the GORD group (p < 0.06). Slow wave activity in both groups remain reduced in comparison to the control group.

Pre prandial brady and tachyarrthymias were more prevalent in the B arrett’s CLO and GORD patient groups, relative to the control group. In the post prandial phase, both brady and tachyarrthymias become more marked in B arrett’s CLO, but were reduced in the GORD patient groups.

This may suggest that DGORD is more marked in the post prandial setting, providing some explanation as to why symptomatic reflux becomes more pronounced in a post prandial setting. An alternative explanation is that the gastric pacemaker has a different setting in different disease states, such that resting activity may be increased in Barrett’s CLO cf GORD and increased activity may occur in the post prandial setting, proportional to GORD.

Increased median antral diameters were noted in the B arrett’s CLO group in comparison to the GORD patient group (p < 0.05) and asymptomatic controls (p <0.05) (Fig. 6.7, 6.8) and in the post prandial setting in all patient groups relative to preprandial values. The increase in antral diameter in the B arrett’s CLO group, was anticipated as a persistently large post prandial antral diameter is suggestive o f dysfunctional relaxation o f the pylorus and thus antroduodenal dysmotility, which is assumed to be more prevalent in Barrett’s CLO relative to the other patient groups.

The combination of both EGG and AU suggest that antroduodenal dysmotility is more prevalent in Barrett’s CLO and this may be intimately related to the increased morbidity associated with the disease.

Bilitec and antroduodenal assessment.

The bilitec has a role to play in the evaluation o f symptomatic GOR, which is refractory to acid suppression, in the presence o f equivocal 24 hour pH analysis. Symptom evaluation, within an alkaline pH range, is notoriously unreliable in view o f the artefacts associated with the release o f bicarbonate from the distal oesophageal submucosal glands, oesophageal stasis and the high alkaline content o f saliva, all o f which may increase the pH o f the refluxate.

The drawbacks associated with the bilitec are that, its use is based on the premise that bilirubin is used as a marker of duodenal contents in the distal oesophagus, as opposed to direct assessment of bile acids, their respective salts and trypsin. In an acidic enviroment (pH < 3.5), absorbance values may be altered by as much as 35 %, in view o f bilirubin dimérisation. In addition, various foods can alter absorbance, hence the need for a standardised diet.

Alternative techniques available for evaluation o f duodenal contents within the distal oesophagus include, scintigraphy which is static and involves the use of radio isotopes or aspiration studies, either manual or automated in combination with reverse phase high performance liquid chromatography.

Data analysis revealed that patients with B arrett’s CLO and GORD, as anticipated, had increased bilirubin absorbance values (Fig. 7.1) and DeMeester scores (Fig. 7.2) and reduced LOS parameters (Fig. 7.3 - 7.6) than an asymptomatic control group. In addition, an increased prevalence o f antroduodenal dysmotility was demonstrated in the Barrett’s CLO and GORD patient groups in comparison to the control group. This may represent the mechanism of delivery o f duodenal contents to the distal oesophagus, under these circumstances. The complementary demonstration o f the increased presence o f bilirubin and antroduodenal dysmotility in B arrett’s CLO and GORD patient groups, may have a potential role in the prediction o f those patients who are at an increased risk o f complications from either disorder, where all other investigations remain equivocal.

Im pedance

Electrical intraluminal impedance (Eli), may enable a more precise evaluation of the refluxate. Although still an experimental tool, it is being used to assess reflux episodes within a non acidic pH range (Skopnik et al, 1996). E li is inversely proportional to the electrical conductivity of the luminal contents and cross sectional area. The conductivity o f the luminal wall and air is negligible and by comparison the conductivity o f a fluid containing bolus is high. In the resting phase, the oesophageal walls are collapsed and are covered by a thin film o f fluid, which results in a high resting Eli. On passage o f a bolus, preceded by air, there is an initial decrease in conductivity and thus a corresponding increase in Eli. The detection of the bolus, with its high conductivity is identified by a reduction in Eli. The characteristic pattern obtained with swallowing enables reliable differentiation from the typical pattern obtained with a reflux bolus. Further differentiation between wave patterns obtained during an acid or non acidic reflux episode are currently being evaluated.

A combined impedance, 24 hour pH catheter enables the simultaneous analysis o f impedance and acid reflux episodes. Symptomatic reflux episodes occurring within a non acidic pH range would theoretically be missed by conventional 24 hour pH monitoring, in the absence o f a comparative method, as pH analysis is dependent on

hydrogen ion detection at the analysing electrode. Impedance is independent o f pH measurement and thus has the potential to increase diagnostic yield (Skopnik et al, 1996).

Conclusions.

There is little acknowledgement in the literature with regard to symptom expression in a non acidic pH range, in particular the neutral (4 - 7) pH range. Data from chapter 4 suggests that 30 % of patients with GORD and 38 % with Barrett’s CLO respectively, experienced the majority o f their symptoms within a neutral (4 - 7) pH range. It is widely acknowledged that 90 % o f bile delivery to the distal oesophagus, arises in the neutral pH range. In addition, alkaline reflux has been significantly implicated in the sequelae of GORD, namely Barrett’s CLO and oesophageal junctional adenocarcinoma.

Effective validation for the present study has been obtained, through the use o f regression analysis data, with efficient discrimination between patients who reflux in an acidic pH range, who demonstrate good symptom correlation (r = 0.68) and poor correlation in the neutral reflux group (r = 0.02) in the GORD patient group.

The inability to reliably identify an isolated physiological parameter essential in the maintenance o f LOS competence, implies that it is the combination of all these factors which are required to maintain LOS integrity.

The reduction in mucosal sensitivity in B arrett’s CLO to acid reflux is readily acknowledged. A reduction in mucosal sensitivity o f the metaplastic epithelium to acid perfusion in comparison to a GORD (p <0.001) and control patient groups (p < 0.001) was confirmed and also to alkaline perfusion, on comparison to a control group (p < 0.01) alone.This may account for the large number o f Barrett’s CLO patients who present de novo with an associated complication such as a junctional malignancy.

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 effective means o f validating data from chapter 5.

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 bum.

Prior sensitization of the mucosa ie the degree of 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. Other relevant factors may include an increased thresh hold in the distal oesophageal sensory receptors for hydrogen ion sensitivity in comparison to bile acids and their salts and an overall reduction in the distribution o f alkaline specific receptors, relative to hydrogen ion receptors.

Antroduodenal dysmotility has been implicated in the pathogenesis o f duodenogastro oesophageal reflux, which is relevant to bile delivery to the distal oesophagus. Non invasive assessment, utilising electrogastrography (EGG) and antral ultrasound demonstrated that median pre and post prandial frequencies fell within normal limits ie slow wave activity was greater than 70 % in all patient groups. This was similar to the data obtained in Leahy and Chen’s original work and thus provide a means o f validation. Marked antroduodenal dysmotility in both B arrett’s CLO (p < 0.01) and GORD (p < 0.01) in the pre and post prandial phases, B arrett’s CLO (p < 0.001); GORD (p< 0.05), were noted in comparison to a control group.

An increased prevalence o f brady and tachyarrthymias were demonstrated in the B arrett’s CLO and GORD patient groups, which were more marked in the postprandial phase. This may partly explain the increased presence o f bile in the oesophageal refluxate in B arrett’s CLO patients and be associated with their recognised increased morbidity. The combination o f bilitec and antroduodenal assessment is suggestive o f this.

Conservative management based on acid suppression is less likely to succeed in the presence o f a mixed or predominantly non acidic refluxate. Relapse rates o f 28 % still occur in patients with severe oesphagitis and B arrett’s CLO, despite double strength