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ORIGINAL ARTICLEBiliary reflux and non-acid reflux are two distinct phenomena:Acomparison between 24-hour multichannel intraesophageal impedanceand bilirubin monitoringFABIO PACE,ORNELLA SANGALETTI,STEFANO PALLOTTA,PAOLA MOLTENI &GABRIELE BIANCHI PORRODivision of Gastroenterology,‘‘L.Sacco’’University Hospital,Milan,ItalyAbstractObjective.Duodenogastroesophageal reflux (DGER)can greatly increase microscopic and macroscopic esophagealmucosal damage caused by acid.The aim of this study was simultaneously to assess the chemical composition of DGER bydetecting bilirubin in the refluxate by means of Bilitec and describe its pH and physical properties by impedancemonitoring,in order to prove that non-acid reflux and biliary reflux are two distinct phenomena.Material and methods.Twenty patients with gastroesophageal reflux disease (GERD)with symptoms refractory to conventional proton-pumpinhibitor (PPI)therapy or with atypical GERD symptoms were included in the study.All patients underwent uppergastrointestinal endoscopy and simultaneous Bilitec and intraeosophageal impedance (IIM)and pH monitoring.In themajority of patients (16/20),the tests were performed while assuming a standard PPI dose.Results.Pathological bilirubinexposure,as defined by intraesophageal bilirubin absorbance above 0.14for more than 3.9%of the time,was present in9cases,6of them with normal values of non-acid reflux,as detected by IIM.A pathological non-acid reflux,as defined byan IIM showing a percentage time with non-acid reflux greater than 1.4%,was observed in 5patients,2of whom hadno pathological biliary reflux,as detected by Bilitec.No correlation was found between the two indices,as expressed by anr -value of (0.12(p 0.05).Conclusions.Our study confirms that biliary reflux and non-acid reflux as detected by Bilitecand by IIM,respectively,are two distinct phenomena that require different techniques in order to be assessed in humans.Key Words:Bilitec,duodenogastroesophageal reflux,GERD,intraluminal impedance monitoring,pH-metryIntroductionAlthough acid reflux is considered the most relevantpathogenetic factor in gastroesophageal reflux dis-ease (GERD),the non-acid component of therefluxate may play a role in inducing esophagealdamage;for instance,it is well known that pepsin,even in small amounts,may greatly increase both themicroscopic and macroscopic esophageal mucosaldamage caused by acid [1Á3].Most studies on non-acid reflux have focused on the importance ofduodenogastroesophageal reflux (DGER)in thegeneration of esophageal damage,complications ofGERD,and recently also on persisting symptomsdespite apppropriate antisecretory treatment [4].Thus,biliary reflux has been shown to have asynergistic role with acid in some patients with Barrett’s esophagus [5,6],in complicated esophagitis [7],and in GERD patients refractory to proton-pump inhibitors (PPIs)[8].Beside these observa-tions,esophageal exposure to isolated bile reflux has been shown to be responsible for reflux esophagitis or Barrett’s development in patients with abolished gastric acid secretion,i.e.after total gastrectomy [9,10].However,as recognized by others [4],substantia-tion of the role of DGER has been hampered by the lack of a ‘‘true’’gold standard by which it can be measured;in fact,many methods have been pro-posed in the recent past,each one with its own particular advantages and disadvantages.Historically,measurement of DGER has been thought to be feasible by scintigraphy,endoscopy,Correspondence:Fabio Pace,MD,Ospedale Polo Universitario ‘‘L.Sacco’’,Via G.B.Grassi 74,IT -20157Milan,Italy.T el:'390239042943.Fax:'390239042337.E-mail:cn.fapac@tin.itScandinavian Journal of Gastroenterology ,2007;42:1031Á1039gastric aspiration techniques,ambulatory gastric pH monitoring,and more recently by endoluminal spectrophotometric techniques(Bilitec)and impe-dance monitoring[4];notably,only the last three methods will allow continuous and physiological measurements to be performed.However,as far as pH-metry is concerned,the use of esophageal pH 7as a marker of DGER,as proposed by Pellegrini et al.[11],is confounded by several problems,and may in fact be considered a misnomer [12];for example,no correlation can be found between the percentage of total time with pH 7 and bile reflux,as measured by a combined ambu-latory pH and bilirubin device(Bilitec)[6].The latter method,i.e.the simultaneous monitor-ing of bilirubin combined with pH monitoring, originally proposed by Bechi et al.[13],provides the most accurate information available with regard to DGER in humans[4].Recently,a new technique has been introduced to study bolus movements in hollow organs like the esophagus,i.e.the intraluminal impedance monitoring(IIM),which allows detection of gastro-esophageal reflux based on changes in resistance to electrical current flow between two or more electro-des,when a liquid and/or gas bolus moves between them[14].The most recent literature contains different definitions of‘‘non-acid’’reflux,which has been used either to indicate DGER events detected at Bilitec monitoring[4]or reflux events diagnosed by IIM when no change in pH,or a pH fall of less than 1pH unit occurs[15].We aimed at simultaneously assessing the chemi-cal composition of DGER by detecting bilirubin in the refluxate by means of Bilitec and describing its pH and physical properties by impedance monitor-ing,in order to prove that non-acid reflux and biliary reflux are two distinct phenomena,which may,or may not,exist together.Based on this hypothesis,we thought that(null hypothesis)if the two techniques were to yield similar results in terms of final categorization of the patient as having or not having a pathologic non-acid reflux,only in5%or fewer cases would the results of the two tests diverge,i.e.in 1out of20subjects.Thus,the number of20patients was a priori selected as the minimum sample needed to reject the null hypothesis,if false,in order to prove that in fact non-acid and biliary reflux are distinct phenomena,requiring different detection techni-ques.We investigated patients with GERD symptoms refractory to conventional PPI therapy and patients with atypical GERD symptoms,since non-acid reflux in these populations of GERD patients may be important[4].Material and methodsPatient selectionThe study was conducted in the motility laboratory of a tertiary center in North Italy;20GERD patients were enrolled(15F,5M,mean age55.7years, range24Á77years).The investigated patients re-present a consecutive series of subjects referred to our laboratory by the family physician for pH monitoring or impedance monitoring,in order to assess the nature of their supposed GERD-asso-ciated symptoms;patients were included in the study provided that they were able to understand the nature of the examinations and to accept them by signing an informed consent form,in accordance with our local Ethics Committee procedures.All patients agreed to participate in the study.Six patients complained of persistent moderate-to-severe heartburn or regurgitation at least three times a week while being treated for at least3months with a standard single dose,or higher doses,of PPI drugs. The complaints of the remaining14patients were mainly atypical symptoms,such as non-cardiac chest pain,chronic cough,hoarseness or sore throat, associated with either heartburn or regurgitation, or both.Exclusion criteria were peptic ulcer disease,pre-vious esophageal,gastric or biliary surgery,previous abdominal or thoracic radiotherapy,active gastro-intestinal(GI)bleeding,presence of esophageal or fundic varices,diabetes mellitus,Zollinger-Ellison syndrome,progressive systemic sclerosis,Raynaud’s syndrome or other vascular diseases,neurological disorders,esophageal or upper small intestinal Crohn’s disease,herpetic or Candida esophagitis, or active neoplastic disease.In addition,all patients with Barrett’s esophagus,or with a large hiatal hernia (i.e.with a diameter greater than4cm)were excluded from the study.All patients underwent upper GI endoscopy and simultaneous Bilitec and IIM and pH monitoring.In the majority of patients(16/20),the tests were performed while assuming a standard PPI dose. Reflux symptomsPatients were asked about the presence,frequency, and severity of heartburn and/or regurgitation and other potentially GERD-related symptoms by means of a questionnaire-based structured interview:symp-toms should occur at least three times a week and be1032F.Pace et al.of moderate to severe intensity in order to be considered eligible for the study.Upper gastrointestinal endoscopyAll subjects underwent upper GI endoscopy5to 14days prior to the ambulatory monitoring of DGER and pH impedance.If necessary,they were sedated by intravenous administration of diazepam (up to10mg).During endoscopy,the presence of esophagitis was noted and graded according to the Los Angeles classification[16].In addition,the presence and extent of a hiatal hernia and Barrett’s esophagus were noted.In all patients,biopsies were taken from the gastric antrum and corpus as a routine procedure to assess the presence of Helico-bacter pylori.No esophageal biopsies were taken. Esophageal multichannel impedance with ambulatory pH monitoringEsophageal pH impedance was recorded by means of a previously described system[17].Briefly,a 2.1-mm diameter catheter was used that comprised six impedance electrode pairs and one antimony pH sensor(Sandhill Scientific Inc.,Highlands Ranch, Colo.,USA);an impedance amplifier delivered ultra low current flow variations in response to intralum-inal impedance changes.The signals from the impedance and pH channels were digitized at 50Hz and stored in a separate datalogger(Sandhill Scientific Inc.).Before the start of the recording,the pH electrode was calibrated using pH4.0and pH 7.0buffer solutions.The pH-impedance probe was transnasally positioned to record pH at5cm proximal to the lower esophageal sphincter(LES) and impedance at3,5,7,9,15,and17cm proximal to the LES in the esophageal body.Gastroesopha-geal reflux was defined as a sequential oral drop in impedance to less than50%of baseline value starting distally(3cm above the LES)and propagat-ing retrogradely to at least the next two more proximal measuring segments.According to the corresponding pH change,impedance-detected re-flux was classified as acid if pH fell below4for at least4s,and non-acid if the reflux episode the pH during dropped at least1pH unit for at least4s but remained between4and7or did not change at all. Notce that our definitions of non-acid reflux are slightly at variance with the definitions of non-acid as synonymous with weakly alkaline reflux,as proposed by a Consensus Report published after the start of our study[18].A pathological non-acid reflux,as defined by the manufacturer of the device as the percentage time with non-acid reflux greater than 1.4%(Sleuth,Instruction Manual;Sandhill Scien-tific Inc.)Measurement of DGERThe fiberoptic spectrophotometer Bilitec†2000 (Synectics,Stockholm,Sweden)was used to quan-tify DGER.The system consists of a miniaturized probe measuring1.5mm in diameter that carries light signals into the esophagus and back via a plastic fiberoptic bundle.Before each study,the probe was calibrated in water.The probe was located5cm proximal to the previously manometrically deter-mined LES.An episode of DGER is defined as an increase in esophageal bilirubin absorbance 0.14 for more than10s[19].Patients were encouraged to maintain normal activity,sleep schedule,and to follow a particular low-fat diet containing light food elements,and which excluded coffee,tea,and fruit juices,in order to prevent interference with the spectrophotometric recording[20].The only liquids allowed were skimmed milk and non-sparkling water.Study protocolThe study was approved by the local scientific committee,and was conducted in accordance with the Declaration of Helsinki II.The study was performed on an outpatient basis after an overnight stay.The Bilitec probe and the pH-impedance catheter were passed transnasally under topical anesthesia,possibly from the same nostril.The probes were then attached with adhesive tape to the subject’s nose and cheek.Data collection devices were connected to the probes and worn on a belt round the patient’s waist.Registration of pH, impedance and DGER lasted for approximately 23.5h,after which the probes were removed and data transferred to a personal computer for analysis (Figure1).Patients recorded the time of food or 0%durationofbiliaryreflux% duration of non-acid refluxepisodesFigure1.Correlation between duration of biliary and non-acid reflux episodes(%recording time).Biliary reflux and non-acid reflux1033fluid consumption and posture changes on a diary card.They were instructed to stay upright during daytime.Patients were instructed to indicate the occurrence of typical(heartburn,regurgitation)or atypical symptoms(cough,chest pain,etc.)by pressing a marker button on the data collection device and by reporting them on the dairy card as well.The meals were standardized;each subject ate three meals during the examinations(breakfast at around0700h,lunch at noon and dinner at1900h). For breakfast,subjects ate milk and bread;for lunch and dinner pasta or rice,white meat or fish or mozzarella(low-fat cheese),bread,and fruit(one apple or pear).The number of kilocalories ingested during the study ranged from1800to2300kilo-calories,with a maximal total daily energy intake of 9600kJ,mostly supplied by carbohydrates( 50%), with a low-fat content(B30%).The diet in our study was similar to that recently described in a study assessing normal values of24-h ambulatory intraluminal impedance and pH-metry in Italian subjects[21].Event markers on the ambulatory IIM-pH monitoring device recorded meal times and posture changes.Data recording was concluded within24h,when the subjects returned to our laboratory.Data analysisThe pH-impedance data were analyzed by Bioview software(Sandhill Scientific Inc.).Bilitec data were analyzed for DGER with the aid of Gastrosoft software(Gastrosoft Inc.;Synectics Medical,Irvine, T ex.,USA).Acid and non-acid reflux,as measured by the IIM'pH device from one site,and DGER as recorded by Bilitec2000from the other site,were quantified separately using the following variables obtained from computerized analysis:number of reflux episodes,number of reflux episodes lasting longer than5min,and fraction of time of acid,non-acid,or biliary reflux.The recording was divided into upright and supine periods.Pathological acid reflux was considered to be present when intraeso-phageal pH was below4for more than5%of the recording time[22].Pathological DGER was con-sidered to be present when intraesophageal bilirubin absorbance was above0.14for more than3.9%of the time[23].Statistical analysisCorrelation between IIM and Bilitec data was done by linear regression analysis and calculation of correlation coefficient(r-value).A p-value of less than5%was chosen as the threshold of significance, with18degree of freedom(since the number of pair observations to be compared is20)[24].The global performance(normal versus abnormal)of the two tests,i.e.IIM versus Bilitec,was compared using the Fisher exact test;a p-value of less than0.05was considered to be significant.ResultsThe demographic and clinical data of the20patients enrolled in the study,as well as the main results of the tests,are presented in T able I.In all instances,although the symptoms of patients have been improved by the therapy to some extent, all subjects had persisting heartburn and/or regur-gitation while being treated with a standard single dose of PPI drugs or higher doses.In all patients, upper GI endoscopy had been performed prior to the start of PPI therapy,in accordance with current guidelines,which suggest endoscopic investigation of patients with GERD symptoms not responding to short courses of PPI therapy[25].In5patients reflux esophagitis was found(3cases of grade A,2 cases of grade B),whereas in the remaining15 patients the esophageal mucosa was grossly normal (T able I).24-h pH monitoring resultsThe individual data concerning esophageal pH monitoring in the20patients are presented in T able II.Since some patients(16/20)were on and some(4/20)were off PPIs,the data are presented as individual values and no mean or median values were calculated.Pathological acid reflux,as defined by a percentage time with intraesophageal pH below 4for longer than5%of the recording time,was present in4subjects,2of whom were under ongoing PPI therapy(patients6and12).In these subjects, the predominant symptom was atypical(chest pain) only in one instance,whereas in the other three subjects the symptoms were heartburn and/or regur-gitation.24-h Bilitec monitoringThe individual data for Bilitec monitoring are presented in T able III.Pathological bilirubin expo-sure,as defined by intraesophageal bilirubin absorbance above0.14for more than3.9%of the time[23],was present in9cases;in four instances it was associated with predominantly atypical symp-toms.For the above reasons,also the Bilitec data were not cumulated and only individual data are presented.1034F.Pace et al.24-h IIMThe individual data concerning IIM are presented in T able IV.Pathological non-acid reflux,as defined by the manufacturer of the device as the percentage time with non-acid reflux greater than1.4%,was observed in5patients.Interestingly,all these sub-jects were receiving ongoing PPI therapy.Two of them were referred to our laboratory because of atypical reflux symptoms.Relationship of24-h Bilitec and IIMThe relationship between percentage time with bilirubin exposure or with non-acid bolus exposure among the20subjects is shown in Figure1.No correlation was found between the two indices, as expressed by an r-value of(0.12(p 0.05). Figure2shows the relationship between the number of biliary reflux episodes as identified by Bilitec versus the number of non-acid reflux episodes,as identified by IIM;again,no correlation could be found between the two parameters(r0(0.012, p 0.05).Finally,Figure3shows the duration of biliary versus non-acid reflux episodes,as percentage time,expressed as individual histograms.The diagnostic performances of Bilitec as com-pared with IIM are summarized in T able V;assum-ing that a Bilitec study is suggestive of abnormal DGER if a global value of 3.9%for bilirubin exposure is found[23],9patients could be diag-nosed as having pathological DGER,6of whom having normal IIM results;conversely,by using the criterion that an IIM study is suggestive of abnormal non-acid reflux if a global percentage time 1.4%is found,5patients could be diagnosed as having abnormal non-acid reflux,2of whom having a normal Bilitec study.Thus,a coincidentally abnor-mal IIM and Bilitec study were found in only3/11 patients with at least one pathological study. DiscussionNon-acid reflux might be of clinical relevance in a number of conditions;for example,it has beenT able II.Individual results of24-h esophageal pH recording.T otal%of GER %of uprightGER%of recumbentGERPat.1 4.48.70.2Pat.20.10.10.0Pat.3 3.3 5.70.3Pat.413.628.70.9Pat.50.10.10.3Pat.6 5.77.00.0Pat.70.10.20.0Pat.8 1.1 1.20.7Pat.9 3.8 5.90.8Pat.100.000Pat.110.70.51Pat.1213.818.90.3Pat.130.40.70Pat.140.10.010Pat.151 1.80.2Pat.16 3.80.007.5Pat.1710.38.312.6Pat.1800.10Pat.19 2.4 3.60Pat.20 2.6 3.80.9Abbreviation:GER0gastroesophageal reflux.T able III.Individual results of24-h Bilitec recording.24-h Biliary reflux%Upright biliary reflux%Recumbent biliary reflux% Pat.120.512.928.4Pat.20.00.00.0Pat.30.00.00.0Pat.459.231.285.3Pat.524.1 6.959.6Pat.6 1.8 2.00.0Pat.70.00.00.0Pat.820.734.47.0Pat.90.40.60.0Pat.10 6.710.70.5Pat.11 2.2 3.80Pat.12 3.4 5.30Pat.13 3.9 3.6 4.4Pat.1448.826.968.2Pat.15 1.5 2.90.00Pat.16 4.27.70.1Pat.1713.410.916.4Pat.180.20.40Pat.19 5.38.90Pat.20 2.9 4.701036F.Pace et al.demonstrated that in GERD patients poorly respon-sive to single-dose PPI therapy,38%had pathologi-cal DGER exposure and 26%had pathologicalDGER and acid reflux,as assessed simultaneouslyby Bilitec and pH-metry [8];in this study,addingthe Bilitec monitoring increased the diagnosis ofpersistent reflux despite therapy from 37%asachieved by pH-metry only,to 75%as achieved byboth techniques.Moreover,the phenomenon ofshifting from a prevalently acid reflux pattern beforetherapy to an almost exclusively non-acid refluxpattern during PPI therapy has already been clearlydemonstrated some years ago by Vela et ingsimultaneous IIM 'pH-metry [26].Furthermore,inthe pathophysiology of Barrett’s esophagus,thepresence of non-acid (i.e.alkaline)components inthe refluxate might aggravate the noxious capacity ofgastroesophageal reflux [5,6],and in this category ofpatients it has recently been demonstrated thatnormalization of esophageal pH,as achieved by PPI therapy,does not guarantee control of DGER [27];in the study by T odd et al.,20out of 25patients with Barrett’s esophagus showed a normal esophageal pH profile while on PPIs,but 55%of them had an abnormal esophageal exposure to bile,as measured by Bilitec [27].Thus,the detection of non-acid and biliary reflux may be important in the investigation of patients with refractory or complicated GERD symptoms,as well as in some with so-called atypical symptoms [28].For example,it has been proposed that in patients with GER who remain symptomatic on PPI therapy,combined pH and multichannel impedance monitoring should be performed during treatment,in order to detect acid as well as non-acid reflux episodes and to correlate symptoms with any epi-sodes of reflux [29].The availability of 24-h ambu-latory techniques such as bilimetry and impedance monitoring has greatly improved our ability to assess the non-acid component of gastroesophageal refluxTable IV .Individual results of 24-h esophageal multichannel impedance monitoring.%Acid reflux total time %Non-acid reflux total timeAcid reflux,no.of episodes Non-acid reflux,no.of episodes Pat.1 1.10.64814Pat.20.0 1.2338Pat.3 1.60.2368Pat.4 3.9 1.24851Pat.50.20.2720Pat.6 1.30.82322Pat.70.1 2.2248Pat.80.6 1.0742Pat.9 1.5 1.11941Pat.100.30.9244Pat.110.30.8739Pat.12 2.50.4361Pat.130.40.3222Pat.140.04 3.34105Pat.150.40.81723Pat.160.30.4537Pat.170.7 4.824104Pat.180 1.6248Pat.190.6 6.9391Pat.20 1.60.825190se d o s i p e x u lf e r d i c a -n o n f o °N N °o f b i l e r e f l u x e p i s o d e s Figure 2.Correlation between number of biliary and non-acidrefluxepisodes.123456123456790111213141516171819102% d u r a t i o n o f r e f l u x (r e c o r d i n g t i m e )Figure 3.Duration of biliary versus non-acid reflux episodes (%recording time)in individual patients.Biliary reflux and non-acid reflux1037in nearly all physiological conditions,thus comple-menting the diagnostic value of pH-metry[18], which has an established role(diagnostic gold standard)in detecting the acid component but no role at all in evaluating‘‘alkaline reflux’’[30]. However,it is not clear whether IIM and bilimetry can be used interchangeably to document and define non-acid reflux,the former being able to character-ize it from the physical(and pH)point of view, whereas the latter from its spectrophotometric as-pect.T o our knowledge,no investigation has been conducted so far using the two techniques simulta-neously.We therefore planned our study to verify the hypothesis that no correlation could exist between non-acid reflux episodes,as detected by IIM,and biliary reflux episodes,as detected by Bilitec.We chose to perform the two tests simultaneously in a reasonably heterogeneous group of GERD patients,including patients refractory to PPI therapy and patients with atypical symptoms,thus represent-ing the ideal sample of patients to be submitted to IIM,according to the current recommendations [28,31].Furthermore,some patients were on and others were off PPI therapy during the tests;under these conditions,it turned out that no correlation at all can be found between the two methods regarding detection and identification of non-acid versus biliary reflux episodes.Intuitively,the main explana-tion for this observation is the fact that,at least in the intact human stomach,biliary reflux can occur at different pH concentrations,including acid values [4],and therefore the change in pH during reflux does not sugges that the presence of bile acids in the refluxate should be suspected.Thus,similarly to what occurred with pH-metry,where it was first proposed and then rejected to use a pH 7as a marker of DGER,IIM cannot be used to assess the biliary content in the refluxate,and the only way to do this is by a direct method such as esophageal aspiration with subsequent chemical analysis[32]or ‘‘in situ’’spectrophotometric determination of bilir-ubin content by Bilitec[13].The practical consequence of our study is that, despite the fact that IIM offers the‘‘opportunity to conceive gastro-oesophageal reflux more broadly,in terms of both frequency and characteristics of the refluxate’’[18],it cannot describe its composition,in particular in terms of biliary content,which can only be afforded by esophageal bilirubin concentration monitoring.Both techniques will ultimately be required in order to characterize a non-acid reflux episode in its physicochemical essence.One potential weakness of our study lies in the relatively small number of patients investigated, which might have influenced the strength of the study itself.Nevertheless,the patient sample (n020)proved to be sufficient to reject the null hypothesis,and therefore to‘‘falsify’’it,enabling the study of enough power to accomplish this goal.In conclusion,our study has confirmed that biliary reflux and non-acid reflux as detected by Bilitec and by IIM,respectively,are two distinct phenomena that need different techniques to be assessed in humans.AcknowledgementsThis paper was presented at the DDW held in Chicago(USA)in May2005.Conflict of interestsNo funding has been received for this work,which was conducted in the setting of normal laboratory activities at the Division of Gastroenterology,‘‘L. Sacco’’University Hospital,Milan.There are no conflicts of interest.References[1]Goldberg HI,Dodds WJ,Gee S,Montgomery C,ZborlaskeFF.Role of acid and pepsin in acute experimental esopha-gitis.Gastroenterology1969;56:223Á30.[2]Johnson LF,Harmon JW.Experimental esophagitis in arabbit model.J Clin Gastroenterol1986;Suppl1:26Á44. [3]Zaninotto G,Di Mario F,Costantini M,Baffa R,GermanaB,Dal Santo PL,et al.Oesophagitis and pH of refluxate:an experiemental and clinical study.Br J Surg1992;79:161Á4.[4]Katz PO.Review article:the role of non-acid reflux in gastro-oesopahgeal reflux disease.Aliment Pharmacol Ther2000;14:1539Á51.[5]Attwood SEA,DeMeester TR,Bremner CG,Barlow AP,Hinder RA.Alkaline gastroesophageal reflux:implications in development of complications in Barrett’s columnar lined lower esophagus.Surgery1989;106:764Á70.[6]Champion G,Richter JE,Vaezi MF,Singh S,Alexander R.Duodenogastroesophageal reflux:relationship to pH andT able V.Global tests results:Bilitec versus IIM.The2)2 contingency table shows the concordance/discordance of Bilitec versus IIM examination in defining the text as normal or abnormal,respectively,regarding the percentage time of biliary reflux or non-acid reflux found(for explanation or definition,see text).Bilitec abnormal (for DGER)*Bilitec normalIIM abnormal(fornon-acid reflux)**32IIM normal69 Abbreviations:IIM0intraluminal impedance monitoring; DGER0duodenogastroesophageal reflux.*NV0B4%recording time[23];**NV0B1.4%recording time (IIM Sleuth-Sandhill manual).1038F.Pace et al.。