01 Presence gas(不要第一页)
doi: 10.1136/gut.2007.130104
2008 57: 443-447 originally published online August 31, 2007
Gut
S Emerenziani, D Sifrim, F I Habib, et al.
physiological acid exposure of the oesophagus
reflux perception in non-erosive patients with Presence of gas in the refluxate enhances
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Presence of gas in the refluxate enhances reflux perception in non-erosive patients with physiological acid exposure of the oesophagus
S Emerenziani,1D Sifrim,2F I Habib,3M Ribolsi,1M P L Guarino,1M Rizzi,1R Caviglia,1 T Petitti,1M Cicala1
1Department of Digestive Diseases,University Campus Bio Medico,Rome,Italy;
2Gasthuisberg University Hospital,Centre for Gastroenterological Research, Leuven,Belgium;3Department of Clinical Science,University La Sapienza,Rome,Italy Correspondence to: Professor M Cicala,Via Longoni 83,00155Roma,Italy;
m.cicala@unicampus.it
Revised27July2007 Accepted14August2007 Published Online First
31August2007ABSTRACT
Objective:The mechanisms underlying symptoms in
gastro-oesophageal reflux disease,particularly in non-
erosive reflux disease(NERD),remain to be fully
elucidated.Weakly acidic reflux and the presence of gas
in the refluxate could be relevant in the pathogenesis of
symptoms.
Methods:To assess the relationship between symptoms
and weakly acidic,acid and mixed(liquid–gas)reflux,
24h oesophageal pH–impedance monitoring was per-
formed in32NERD and in20oesophagitis patients.In12
NERD patients the study was repeated following4weeks
treatment with a proton pump inhibitor(PPI).Impedance–
pH data were compared with those of10asymptomatic
controls.Heartburn and acid regurgitation were consid-
ered in the analysis of symptoms.
Results:15NERD patients showed a physiological acid
exposure time(pH-negative).Weakly acidic reflux was
significantly less frequent in patients(25%(2%),mean
(SE))than in controls(54%(4%),p,0.01).Gas was
present in45–55%of reflux events in patient groups and
controls,and decreased following PPI treatment.In NERD
pH-negative patients,weakly acidic reflux accounted for
32%(10%)(vs22%(6%)in NERD pH-positive and12%
(8%)in oesophagitis patients)and mixed reflux for more
than two-thirds of all symptom-related refluxes.
Multivariate logistic analysis showed that in NERD pH-
negative patients,the risk of reflux perception was
significantly higher when gas was present in the refluxate
(odds ratio,3.2;95%CI,1.2to10;p,0.01).
Conclusions:The large majority of symptoms,in all
patients,are related to acid reflux.In NERD patients,the
presence of gas in the refluxate significantly enhances the
probability of reflux perception.These patients are also
more sensitive to less acidic reflux than oesophagitis
patients.
The pathogenesis of heartburn and acid regurgita-
tion still remains to be fully elucidated,particularly
in the large group of gastro-oesophageal reflux
disease patients not exhibiting oesophageal muco-
sal injury at endoscopy,namely the non-erosive
reflux disease(NERD)patients,whose24h pH
test often remains within the normal range.1–3
Indeed,several studies have demonstrated that
NERD patients are less sensitive to proton pump
inhibitor(PPI)treatment than patients with
erosive reflux disease(ERD).4–6One of the most
common clinical findings in these patients is
hypersensitivity to visceral stimulation,which is
characterised by a reduced pain threshold to
experimental stimulation.78It has been suggested
that dysfunction of visceral neural pathways and/
or alterations in central pain processing of visceral
stimuli may contribute to produce and mediate
oesophageal visceral hypersensitivity in patients
with symptoms but no evidence of endoscopic or
pH monitoring abnormalities.9Recent pH–impe-
dance studies have shown that weakly acidic reflux
may be associated with symptoms of oesophageal
and extraoesophageal gastro-oesophageal reflux
disease,particularly during PPI treatment.1011
However,so far,no studies have focused on a
comparison of the relationship between weakly
acidic reflux and typical gastro-oesophageal reflux
disease symptoms in NERD and in ERD patients.
Heartburn does not appear to be stimulus
specific.Prolonged pH monitoring studies reveal a
poor correlation between acid reflux episodes and
heartburn sensation;12it has been reported that
acute acid exposure of the oesophagus enhances
the oesophageal perception to intraluminal balloon
distension and that oesophageal distension induces
heartburn and chest pain.13–15Moreover,it has
recently been demonstrated that heartburn,but
not chest pain,in normal subjects is the most
common response to oesophageal distension,and it
seems that the distension-induced sensation is
mediated through stretch mechanoreceptors.16
The composition and volume of refluxate can
affect its proximal extent and the degree of
oesophageal distension.1718
Oesophageal pH–impedance monitoring can
accurately identify less acidic or even non-acid
reflux,with or without a gas component.19This
technique detects at least95%of all reflux episodes
and it has been demonstrated to be reproducible.20
Therefore,the aim of this study was to assess the
symptom–reflux association according to acidity
and composition(liquid–gas)of refluxate in NERD
patients,with and without excessive oesophageal
acid exposure,when compared with ERD patients.
METHODS
From January2005to January2006,60consecutive
patients complaining of typical gastro-oesophageal
reflux disease symptoms—heartburn and/or acid
regurgitation—lasting.12months,with a history
of a favourable response to PPI treatment(.50%
symptom improvement at standard or double doses)
and of an early relapse after PPI discontinuation,
were invited to take part in the study.All patients
underwent upper endoscopy,stationary oesophageal
manometry and24h pH–impedance monitoring,
the latter performed3–14days(median5days)after
Oesophagus
endoscopy.Following upper endoscopy,five patients were excluded from the study due to duodenogastric peptic disease and/or Barrett’s oesophagus,and three patients presenting with NERD were excluded because of evidence of erosive oesophagitis at previous(3–5years)endoscopy.Of the remaining52enrolled patients,32were NERD patients(16male,16female,median age 41years,range31–57)and20patients(11male,9female,median age54years,range34–59)showed erosive oesophagitis(grade I, n=12;grade II,n=8,according to a modified Savary–Miller classification).Impedance–pH data were compared with those of 10asymptomatic,hospital staff volunteers(6male,4female, median age34years,range31–47)(healthy control group),all non-smokers.
Healthy controls did not differ from NERD patients in term of mean age,but they were significantly younger than ERD patients.
None of the patients had undergone previous gastrointestinal surgery or was taking medication known to influence oesopha-geal motor function.Patients on antisecretory drugs stopped the treatment at least2weeks prior to the study(mean5weeks, range2.8–8).
All NERD patients were invited to undergo a repeated pH–impedance study while on PPI treatment(esomeprazole40mg once a day);12of them agreed(5male,7female,median age42 years,range32–50),and the study was performed following at least4weeks(range4–5)of treatment.
The study protocol was approved by the Ethics Committee of University Campus Bio Medico of Rome,and written informed consent was obtained from all individuals.
Intraluminal electrical impedance and pH
Intraluminal electrical impedance was recorded with a2.3mm diameter polyvinyl assembly containing a series of cylindrical electrodes,each4mm in axial length,spaced at2cm intervals. Each pair of electrodes formed a measuring segment,2cm in length,corresponding to one recording channel(Sandhill Scientific Inc.,Highlands Ranch,CO).The signals from the impedance and pH channels were digitised at50Hz and stored in a separate data logger(Sandhill Scientific Inc.).Oesophageal and gastric pH were measured with an antimony pH electrode. The pH electrodes were calibrated using pH4.0and pH7.0 buffer solutions before beginning recording and at the end of the recording.
Patients and controls were studied after an overnight fast of at least10h.Prior to the ambulatory study,all subjects underwent stationary oesophageal manometry to locate the lower oesophageal sphincter(LOS).Following stationary manometry,the combined pH–impedance assembly was passed through the nose under topical anaesthesia and positioned with the pH electrodes at5cm above the LOS and10cm below the LOS.In this position,impedance was measured at3,5,7,9,15 and17cm proximal to the LOS.Patients and controls were asked not to lie down during the day,but to lie down only at their usual bedtime.Furthermore,patients were instructed to consume three meals and two beverages at fixed times during the24h measurement period.Event markers,on the monitor, recorded meal times and posture changes.
Data analysis
In the analysis of impedance tracings,liquid reflux was defined as a retrograde50%drop in impedance starting distally(above the LOS)and propagating at least to the next two more proximal impedance measuring segments.Gas reflux was defined as a rapid(3k V/s)increase in impedance.5000V, occurring simultaneously in at least two oesophageal measuring segments,in the absence of swallowing.Mixed liquid–gas reflux was defined as gas reflux occurring immediately before or during a liquid reflux.Pure gas reflux was defined as a rapid(3k V/s) and pronounced rise in impedance that moved in a retrograde direction over at least two consecutive impedance sites. Changes in oesophageal pH during reflux detected by impe-dance allowed classification of reflux into:(1)acid reflux—refluxed gastric juice with a pH,4,which can either reduce the pH of the oesophagus to,4or occur when oesophageal pH is already,4;(2)weakly acidic reflux—reflux events that result in an oesophageal pH between4and7;and(3)weakly alkaline reflux—reflux episodes during which nadir oesophageal pH does not drop below7.21
Acid exposure time(AET)was defined as pathological if the time at pH,4exceeded5%of total recording time.Heartburn and acid regurgitation were considered in the analysis of symptoms.Reflux episodes were classified as symptom-related if they occurred(2min before the onset of the symptom.The symptom association probability(SAP)index was calculated according to the formula described elsewhere.22
Statistical analysis
Data were expressed as mean,range or SEs,or95%CIs when required.Analysis of variance(ANOVA)was used to compare the characteristics of reflux events between the groups and in NERD patients off and on PPI treatment.The relationships between the presence of gas in the refluxate and symptoms was analysed using logistic regression models.As reflux events were intrapatient dependent,patients were treated as clusters and the reflux episodes were considered as random samples within the clusters.Logistic regression models for surveys were used. The model was controlled for acidity of refluxate.Moreover,a sampling weight was added as(1)/(number of reflux events within a patient),so that the sum of the weights for a patient was1.23Odds ratio(OR)results of logistic regression were used as relative risk estimators.All statistical analyses were performed using STATA H Statistical Software(Stata Corporation,College Station,
TX).
Figure1Frequency(mean(SE))of acidic and weakly acidic reflux in gastro-oesophageal reflux disease subgroups and controls.*p,0.01vs controls.
Oesophagus
RESULTS
Acidity and composition of reflux in gastro-oesophageal reflux disease patients and healthy controls
Of the 32NERD patients,17(8male,9female,mean age 42years)showed a pathological AET at the distal oesophagus (NERD pH-positive,mean AET 15%,range 5.1–27.2%)and 15patients (4male,11female,mean age 37years)showed a normal pH-metric profile (NERD pH-negative).All ERD patients showed a pathological AET (mean 21%,range 6.7–35.5%).A total of 2984reflux events were detected at the distal oesophageal level:mean 28(range 18–43)in the healthy controls,56(14–104)in NERD,41(14–83)in NERD pH-negative,56(26–109)in NERD pH-positive and 81(32–176)in ERD.The frequency of pure gas and weakly alkaline reflux was very low and,therefore,not further analysed.The frequencies of acidic and weakly acidic reflux in gastro-oesophageal reflux disease groups and healthy controls are shown in fig 1.Gastro-oesophageal reflux disease patients presented significantly higher numbers of acidic reflux episodes compared with healthy controls;weakly acidic reflux was significantly less frequent in patients than in healthy controls.Nearly two-thirds of weakly acidic reflux occurred during the post-prandial periods.
The composition of reflux in gastro-oesophageal reflux disease groups and controls is shown in fig 2.Mixed reflux accounted for 45–55%of total refluxes in all groups.
Symptom–reflux analysis
Of the 32NERD patients,25reported 247symptoms during the study (mean 9,range 1–25),and of the 20ERD patients,13reported 72symptoms (mean 4,range 1–16).Heartburn accounted for 70%and regurgitation for 30%of symptoms.Heartburn accounted for 68%of pure liquid and 76%of mixed symptom-related refluxes.Belching was rarely reported (2out of 25patients)and was not included in the symptom analysis.SAP was positive in 16of the 25NERD patients (7out of 11NERD pH-negative patients,9out of 14NERD pH-positive patients)and in 6of the 13ERD patients.
The frequency of symptom-related and non-symptom-related reflux,according to composition of refluxate,is shown in table 1.
The frequency of symptom-related reflux according to acidity and composition of refluxate is shown in figs 3and 4.In NERD pH-negative patients,weakly acidic reflux accounted for 32%(10%)(vs 22%(6%)in NERD pH-positive and 12%(8%)in ERD patients,p ,0.05vs ERD)and mixed reflux accounted for more
than two-thirds of all symptom-related refluxes.Multivariate logistic analysis showed that,controlling for acidity of refluxate,only in NERD pH-negative patients was the risk of reflux perception significantly higher when gas was present in the refluxate (p ,0.01)(table 2).
Reflux pattern off and on PPI treatment
In all 12patients who repeated the study on a PPI,the analysis of gastric pH confirmed the compliance and the effectiveness of treatment,and the AET at the distal oesophagus was within the normal range.The number of total reflux episodes decreased,non-significantly,from 492(mean 41,range 15–108)off therapy to 428(mean 36,range 6–95)on PPIs;the frequency of weakly acidic reflux significantly increased from 22%(95%CI:19%to 26%)to 69%(95%CI:64%to 73%)(p ,0.001).Mixed reflux accounted for 52%of all reflux episodes (95%CI:41%to 62%)off therapy and decreased to 40%(95%CI:29%to 51%)on therapy (p ,0.05).The decreased frequency of mixed reflux was observed in 9out of the 12patients and it was unchanged in the remaining 3patients.
All patients who underwent repeat pH–impedance investiga-tion reported typical symptoms during the first study (112symptoms,mean 10,range 3–33).Of these,4patients experienced symptoms during the study while on PPI treatment (8symptoms:6regurgitation and 2heartburn episodes;mean 2,range 1–3).
DISCUSSION
Although gastric acid plays a pivotal role in the pathogenesis of gastro-oesophageal reflux disease,other stimuli are believed to be involved in the pathogenesis of typical symptoms.This is more likely in the large group of NERD patients,approximately 50%of them showing a normal oesophageal acid exposure,and/or not exhibiting a significant association between acid reflux and symptoms at ambulatory pH test,but the majority of them responding,even if to a lesser degree than ERD patients,to a PPI given at a single or double dose.
In agreement with a recent multicentre study carried out on patients reporting typical and atypical gastro-oesophageal reflux disease symptoms,with no information available concerning endoscopic findings,11weakly acidic reflux in our gastro-oesophageal reflux disease population (NERD and ERD patients)was less frequent than in healthy controls.This same finding was first reported by Sifrim et al in a well selected gastro-oesophageal reflux disease population even if a liquid meal was chosen during the test.24Of interest,in our series,although the large majority of symptoms were related to acid reflux,NERD patients,particularly those with a physiological acid exposure,were significantly more sensitive to weakly acidic reflux than ERD patients:weakly acidic reflux was responsible for 24%and 32%of all symptomatic episodes,respectively,in all NERD patients and in the pH-negative subgroup.Previous studies carried out on patients off therapy,complaining of symptoms suggestive of gastro-oesophageal reflux disease,11or selected on the basis of a positive symptom–reflux correla-tion,2526showed that weakly acidic reflux accounts for a minority of typical symptoms.Similar findings would have been observed in our entire gastro-oesophageal reflux disease population if patients had not been classified according to endoscopic and pH results.
In the present study,in keeping with previous findings,23no difference in terms of reflux composition was observed between healthy controls and patients or between disease
subgroups.
Figure 2Frequency of mixed and liquid reflux (mean (SE))in controls and gastro-oesophageal reflux disease patients.
Oesophagus
Moreover,we analysed,for the first time in NERD,the reflux composition in the same patients off and on PPI treatment.The results derived from a small group of patients indicated a decreased frequency of mixed reflux in most patients following PPI treatment,although the total number of reflux episodes was fairly similar.We have no explanations for this finding,and its possible role in symptom resolution remains unclear in our
population of PPI responder patients.
Interestingly,in NERD patients with physiological acid exposure of the oesophagus,the presence of gas in the refluxate significantly enhanced the probability of reflux perception.At present,only two studies have focused on the relationship between reflux composition and symptoms in gastro-oesopha-geal reflux disease patients.Bredenoord et al,in patients complaining of typical symptoms,observed a gaseous compo-nent in the refluxate with comparable frequency in both asymptomatic and symptomatic reflux episodes.23In the second study,from the same group,patients were enrolled if they exhibited a significant association between acid reflux and symptoms(SAP).24Compared with controls,the authors found a higher incidence of liquid and mixed reflux only in patients with excessive acid exposure.In these two studies,patients were not classified,as here,according to endoscopic findings.In the present study,patients were consecutively enrolled on the basis of their typical symptoms and their positive,although not always complete,response to acid-suppressive treatment, reflecting the majority of cases with NERD and still classified as having gastro-oesophageal reflux disease,irrespective of their symptom–reflux association,in the new Rome III consensus report for functional oesophageal disorders.27Indeed,a recent report,aimed at assessing the accuracy of symptom–reflux association tests in predicting PPI response,revealed their poor negative predictive values.28In order to assess the relationship between reflux characteristics and its perception,tracings were carefully analysed for each reflux event and symptom occur-rence;moreover,the probability of reflux perception(OR)was calculated by means of multivariate logistic regression.
At present,direct estimation of reflux volume is not feasible in physiological conditions.It is likely that the presence of gas in addition to liquid increases the volume of refluxate and,thus, the degree of oesophageal distension.Previous studies evaluat-ing the effect of oesophageal acid perfusion on perception of oesophageal distension in healthy controls and patients showed that acid perfusion of the oesophagus enhances sensitivity to oesophageal balloon distension.1329In contrast,DeVault et al reported that a15min acid perfusion had no significant effect on pain perception during oesophageal distension;30Trimble et al reported an enhanced sensation and discomfort following oesophageal distension in gastro-oesophageal reflux disease patients with normal acid exposure time compared with patients with pathological pH-metry or Barrett’s oesophagus.8In a more recent study,the effect of acid infusion on sensitivity to oesophageal distension was related to gastro-oesophageal reflux disease severity:although short-term acid exposure of the healthy oesophagus resulted in sensitisation of both mechan-oreceptors and chemoreceptors,only the chemical hypersensi-tivity persisted following long-term acid exposure associated with moderate tissue injury,whereas mechanosensitivity returned to normal.14In keeping with these latter two studies, our results showed that the presence of gas in the refluxate significantly enhances the probability of reflux perception only in NERD patients with physiological acid exposure of the oesophagus,in whom weakly acidic reflux is also highly perceived.
One of the most common clinical findings in NERD patients is hypersensitivity to visceral stimulation,and results from the present study—that is,hypersensitivity to weakly acidic reflux and to mixed reflux—further support this finding.89 Accordingly,increasing evidence indicates an overlap between NERD and functional gastrointestinal disorders,such as functional dyspepsia and irritable bowel syndrome.3132Further studies,evaluating the relationship between composition and perception of reflux in patients not responding to PPIs,would better demonstrate the clinical impact of our findings.
At present,impedance–pH monitoring is the only method to detect gas and weakly acidic reflux and,therefore,seems to be
Table1Frequency(mean(SE))of symptom-related reflux and non-symptom-related reflux,according to composition of refluxate
Symptom-related refluxes Non-symptom-related refluxes
(n)Liquid(%)Mixed(%)Liquid(%)Mixed(%)
All NERD(187)36(6)64(5)*47(4)52(4) NERD pH+(127)40(8)60(8)47(5)52(5) NERD pH2(60)28(10)72(9)*46(7)53(7) ERD(63)48(10)51(9)52(5)47(5)
*p,0.05.
ERD,erosive reflux disease;NERD,non-erosive reflux
disease.
Figure3Frequency of reflux-related symptoms(mean(SE))according
to the acidity of the refluxate in non-erosive reflux disease(NERD)and
erosive reflux disease(ERD)patients.*p,0.05vs
ERD.
Figure4Frequency of reflux-related symptoms(mean(SE))according
to the composition of the refluxate in non-erosive reflux disease(NERD)
and erosive reflux disease(ERD)patients.*p,0.05vs ERD. Oesophagus
useful to confirm the diagnosis in NERD patients,particularly in the pH-negative patients,who are also known to respond to a lesser degree to antireflux treatment.5
In conclusion,the large majority of symptoms,in all patients, are related to acid reflux.In NERD patients with physiological acid exposure of the oesophagus,the presence of gas in the refluxate significantly enhances the probability of reflux perception.NERD pH-negative patients are more sensitive to weakly acidic reflux than ERD patients.It can be hypothesised that these findings offer an explanation for the reduced response to PPI treatment frequently observed in these patients. Acknowledgements:The authors are grateful to Mrs Marian Shields for help with the preparation of the manuscript.
Competing interests:None.
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Table2Odds ratio(OR)of reflux perception in mixed
refluxes with respect to liquid refluxes
OR(95%CI)
All NERD 2.0(1to3.9)
NERD pH+ 1.3(0.6to2.9)
NERD pH2 3.2(1.2to10)
ERD 1.3(0.7to2.4)
ERD,erosive reflux disease;NERD,non-erosive reflux disease.
Oesophagus