Roman S, Gyawali CP, Savarino E, et al. Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: Update of the Porto consensus and recommendations from an international consensus group // Neurogastroenterol Motil. 2017;29:e13067.
Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: Update of the Porto consensus and recommendations from an international consensus group
S. Roman1, C.P. Gyawali2, E. Savarino3, R. Yadlapati4, F. Zerbib5, J. Wu6, M. Vela7, R. Tutuian8, R. Tatum9, D. Sifrim10, J. Keller11, M. Fox12, J.E. Pandolfino4, A.J. Bredenoord13, the GERD consensus groupa
1Digestive Physiology, Hospices Civils de Lyon and Lyon I University, Inserm U1032, LabTAU, Lyon, France.
aGERD consensus group: Fernando Azpiroz, Arash Babaei, Shobna Bhatia, Guy Boeckxstaens, Serhat Bor, Dustin Carlson, Donald Castell, Michele Cicala, John Clarke, Nicola de Bortoli, Vasile Drug, Marzio Frazzoni, Richard Holloway, Peter Kahrilas, Arne Kandulski, Phil Katz, David Katzka, Ravinder Mittal, Francois Mion, Luis Novais, Amit Patel, Roberto Penagini, Mentore Ribolsi, Joel Richter, Renato Salvador, Vincenzo Savarino, Jordi Serra, Felice Schnoll-Sussman, Andre Smout, Edy Soffer, Rami Sweis, Jan Tack, Salvatore Tolone, Michael Vaezi, Philip Woodland, Yinglian Xiao.
Correspondence: Sabine Roman, Digestive Physiology, Hopital Edouard Herriot, Lyon, France. Email: sabine.roman @ chu-lyon.fr
Funding Information: The consensus process was supported by the Working Group for Gastrointestinal Motility and Function. This group received an educational grant of United European Gastroenterology (UEG).
Gastro-esophageal reflux disease (GERD) is defined as a “condition which develops when the reflux of gastric content causes troublesome symptoms or complications”. A large proportion of patients are treated empirically with acid suppressant drugs. Further investigation is mainly indicated in patients with warning signs, atypical symptoms, lack of response to pharmacological therapy or prior to invasive endoscopic or surgical procedures. While upper gastro-intestinal endoscopy is the first line examination to evaluate reflux consequences (esophagitis, Barrett's mucosa) and to rule out conditions mimicking reflux symptoms (e.g. tumors, strictures), this cannot measure reflux itself or provide definite evidence that symptoms are caused by reflux; instead, ambulatory reflux monitoring is required for this purpose. The 2004 Porto consensus provided recommendations for reflux definition and detection. Wireless pH monitoring and pH-impedance monitoring were introduced only a few years prior. Since then, monitoring techniques have rapidly gained ground and numerous publications have provided new insights, warranting an update of the Porto consensus.
An international group of experts proposed to revise recommendations for ambulatory reflux monitoring for GERD diagnosis. The conclusions of the working group are presented here.
Following the model of the Chicago Classification for definition of esophageal motility disorders in high resolution manometry (HRM), an international group of experts convened at five distinct meetings (UEGW 2014, Ascona 2015, UEGW 2015, DDW 2016 and UEGW 2016) to establish and discuss guidelines for GERD testing based on extensive literature search. The search was focused on indications for GERD testing, technical recommendations for data acquisition and analysis of esophageal pH and pH-impedance monitoring, and GERD phenotypes. Statements for GERD testing were thus proposed and graded on the quality of the supporting evidence according to the GRADE system (Table 1). The strength of the individual statements is based on the aggregate evidence quality and a balance between benefits and harms. GRADE category is indicated in the text within parenthesis in italics and in Tables; details are provided in Data S1.
Grading of recommendations assessment, development, and evaluation (GRADE) system for the quality of evidence for guidelines
3. Indications for GERD testing
3.1. Indications of pH and pH-impedance monitoring
GERD testing is usually performed when there is a need for a definite diagnosis of GERD. It may be indicated in patients with incomplete or lack of response to PPI therapy,[4-6] prior to and/or following anti-reflux surgery,[7, 8] and for atypical symptoms like cough, frequent belching, and suspected rumination [9-11] ( ).
Recommendations are provided in Table 2 to guide the modality of GERD testing. The use of 24-hours esophageal impedance-pH monitoring is currently considered as the gold standard for the detection of reflux episodes, since impedance measurement permits the detection of anterograde and retrograde bolus (liquid, gas, or mixed) flow in the esophagus and combined-pH monitoring allows the chemical characterization of the refluxate.[2, 12] Therefore, compared to pH-based reflux monitoring alone, pH-impedance monitoring can detect not only acidic (pH<4) but also weakly acidic (4≤pH<7), weakly alkaline (pH≥7), gaseous, and re-reflux episodes.[13-16] This definitely increases the diagnostic yield of reflux monitoring in patients with GERD.[17, 18] However availability, cost and patient preference may drive the choice between catheter based pH, pH impedance or wireless pH monitoring.
Recommendations for the choice of GERD testing
Specific indications for wireless pH monitoring include intolerance of the transnasal catheter () [20, 21] or a negative catheter based pH study with high suspicion of GERD, to elicit day to day variation in acid exposure and for improving detection of symptom association ( ).[22-24] Prolongation of pH monitoring beyond 24 hours increases sensitivity of reflux detection and symptom events for symptom reflux association.[25, 26]
In case of incomplete or no response to PPI therapy in patients with a high probability of reflux disease, GERD testing is performed on medication. This determines whether the patient is refractory to PPI therapy by quantifying reflux burden on medication, and assesses whether reflux and symptoms are related in time.[15, 27] Thus, using combined impedance-pH monitoring is useful to determine if PPI failure is associated with (i) ongoing acid reflux, (ii) adequate acid control but ongoing symptomatic non-acid reflux, or (iii) no reflux.[15, 27-31]
While pH-monitoring is recommended before anti-reflux surgery, there are limited data on the incremental value of adding impedance to pH monitoring to facilitate selecting patients for anti-reflux surgery, and even less data on the indication for surgery based on the number of reflux episodes alone.[32-35] Good surgical outcomes (in terms of patient satisfaction) have been reported when using abnormally high total number of reflux episodes detected by impedance off therapy (in patients with normal pH parameters) as a means of selecting patients for antireflux surgery. This was also demonstrated in patients who were studied on PPI.[34, 37, 38] However, these studies lack control groups; there is also no information on whether patients with low total number of reflux episodes perform poorly after antireflux surgery. Furthermore, others found that abnormal pH values and “typical” reflux symptoms were better predictors of a positive outcome after antireflux surgery compared to results of impedance testing off or on medication.[33, 39, 40] Consequently, data are insufficient to recommend antireflux surgery based solely on an increased number of reflux episodes detected by impedance ().
In the evaluation of patients who report recurrent symptoms after surgery, the yield of pH-impedance testing over pH-only monitoring is variable. Some authors suggested that symptoms were driven by weakly acid reflux episodes while others found that reflux episodes detected by impedance monitoring were not significant contributors of symptoms.[32, 41] Interestingly one study demonstrated that supragastric belching was the cause of recurrent symptoms after surgery in a third of patients. Moreover, the severity of post-surgery gas-related symptoms was not associated with an increased number of pre-operative air swallows and/or belches or a larger post-operative decrease in the number of gastric belches. In absence of clear data in the literature, the working group recommends the same reflux monitoring modality that was performed prior to surgery be performed following surgery off of PPI ( ).
Establishing a relationship between chronic cough and reflux is challenging. Chronic cough can be associated with weakly acidic reflux, thus favoring the use of impedance-pH rather than pH alone in this particular setting.[43-47] A cough detector or ambulatory manometry can be an important tool to distinguish cough-reflux and reflux-cough sequences. However, in the absence of outcome data, it is difficult to determine which patients with chronic cough associated with reflux would benefit from anti-reflux surgery.
Excessive belching is a common phenomenon observed in patients with GERD or functional dyspepsia. Esophageal impedance reliably distinguishes gastric belch episodes from supragastric belch episodes. Interestingly, supragastric rather than gastric belching is frequently encountered in patients with complaint of excessive belching.[10, 48] Thus, impedance-pH monitoring may be considered the “gold standard” for the workup of patients with excessive belching. When performed in conjunction with manometry, impedance can also be used to distinguish rumination syndrome from GERD-related regurgitation in patients with normal lower esophageal sphincter (LES) function who have emesis without antecedent retching as in rumination a gastric pressure increase >30 mm Hg will precede the occurrence of reflux.[49, 50]
3.2. Testing off or on PPI
Determining if GERD testing is to be performed off or on PPI therapy is an important initial decision point in esophageal physiologic testing.[7, 51] Testing off PPI results in more symptoms reported during the measurement and thus a higher yield of symptom-reflux association analysis. Testing off PPI also reveals the naïve esophageal acid exposure time. On the other hand, in some instances one would like to know why the treatment for GERD is not effective and whether complete acid suppression is obtained. The decision should be made with consideration of the patient's clinical presentation and pre-test evidence for reflux (Figure 1).
Figure 1. Algorithm describing when gastro-esophageal reflux disease testing should be performed off or on treatment with proton pump inhibitors (PPI)
Reflux monitoring (catheter based pH, wireless pH, or pH impedance) should be performed off PPI to confirm if the question is whether reflux is the cause of symptoms and if patient truly has GERD in case of non-response to therapy (). This is also the case when testing prior to antireflux surgery ( )  in the setting of persistent symptoms in patients with non-erosive reflux disease (normal esophageal mucosa), grade A or B esophagitis, Barrett's esophagus (defined as intestinal metaplasia on esophageal biopsies) segments (<1 cm), atypical presentations, absent or incomplete response to PPI, and recurrent/persistent symptoms after anti-reflux surgery.
In patients with prior evidence of excessive reflux (prior positive pH testing, esophagitis, Barrett's esophagus >1 cm or peptic stricture) the main question is not whether there is GERD but why the treatment is failing. In this case impedance-pH testing should be performed on PPI in search of ongoing reflux (either acid or non-acid) despite PPI ().
4. Performing pH and pH-impedance monitoring: recommendations for data acquisition
Instructions to be provided to patients for data acquisition are summarized in Table 3. All of them are based on expert recommendations in absence of clear evidence in literature.
Recommendations for data acquisition of pH and pH-impedance monitoring
By convention, the pH or pH impedance catheter is positioned with the distal esophageal pH probe 5 cm above upper border of the manometrically defined lower esophageal sphincter (LES) for catheter based monitoring, as up to 2 cm of movement in either direction can be expected with swallowing and head movement, and this location reduces catheter migration into the stomach. The wireless probe is positioned transorally 6 cm proximal to the squamocolumnar junction identified during endoscopy (or 9 cm above upper border of the manometrically defined LES from the nostrils), which corresponds to the conventional pH positioning 5 cm proximal to the LES.[22, 53]
5. Interpreting pH monitoring
Recommendations for data analysis are reported in Table 4.
Recommendations for the analysis of pH and/or pH-impedance monitoring
5.1. pH thresholds defining pathological distal esophageal acid exposure
A drop in esophageal pH below 4 is the most discriminative threshold to define a reflux episode.[54, 55] By cumulative summation of time when esophageal pH is below 4, the acid exposure time (AET, % time with pH<4 over the study duration) can be derived. Meal times, fluid ingestions, and artifacts are typically excluded, as ingested acidic material can confound the calculation. A general visual inspection of pH study should be performed to exclude artifacts and to search for catheter displacement or wireless capsule dislodgment, especially in case of high AET.
A composite parameter taking six individual metrics, total AET, upright AET, recumbent AET, number of reflux episodes, reflux episodes with pH<4 for ≥5 minutes, and duration of longest reflux episode, is described as the DeMeester score. Of these, the total AET is the most reproducible  and AET overall is more specific compared to other individual components of the DeMeester score. By consensus, the AET is favored as the metric used to designate esophageal acid burden, and elevated AET has been demonstrated to predict a positive response to PPI trial,[47, 59, 60] and symptom outcome following antireflux therapy.[38, 40]
On catheter based pH monitoring off antisecretory therapy, mean total AET values and 95th percentile of normal have ranged from 3.9% to7.2% in patients who are either asymptomatic or with occasional (<2 episodes/month) heartburn symptoms, with sensitivity of 77%-100% and specificity of 85%-100% in discrimination of esophagitis from normal controls.[55, 58, 61-67] Based on these data, a total AET value of <4% is consistently normal () and less than 6% is likely to be normal (Figure 2). In contrast, patients with erosive esophagitis have mean total AET of 9.6%-27.6%.[55, 58, 61, 62, 64, 66] Thus, the consensus group concluded that AET >6% was consistently abnormal ( ). There is consistent overlap between normal controls and symptomatic GERD without esophagitis within a gray area consisting of 95th percentile AET values of 4%-6%,[57, 62, 68, 69] where additional evidence from alternate testing may provide further confidence in the presence of pathologic acid burden ( ). Furthermore, there is considerable day-to-day variability in AET measurements so a clinical decision should never be made exclusively based on this parameter.[70, 71]
Figure 2. Definition of pathological gastro-esophageal reflux disease according to findings on upper gastro-intestinal endoscopy, 24-hours pH monitoring and 24-hours esophageal pH-impedance monitoring. Additional testing should be considered in case of borderline examination. AET, acid exposure time
Wireless pH monitoring is associated with marginally higher 95th percentile AET values in normal controls (4.4%-5.3%),[22, 72, 73] but within the gray area indicated above. Therefore, similar concepts can be applied to distal AET thresholds with wireless pH monitoring as for catheter based pH monitoring. Using wireless pH-monitoring, analysis could be performed at every day separately taking into account the worst day or averaging the entire study period. While sensitivity is obviously higher with worst day analysis, specificity is obviously higher with averaged AET.[26, 71]
5.2 Upright and supine acid exposure time
Abnormal supine AET is observed in different conditions: poor sleep quality, severe erosive esophagitis, Barrett's esophagus,[74-76] elevated BMI, and consumption of a late-evening meal. Pre-operative pathological bi-positional (upright and supine) AET may have higher likelihood of recurrent pathological acid exposure and esophagitis following Nissen fundoplication and the need of re-operation, but the results are conflicting.[79-81]
While upright and supine AET might differ according to associated conditions, further studies are needed to evaluate the value of additional reporting of acid exposure time during sleep.
5.3 Proximal acid esophageal exposure
Dual sensor pH monitoring was proposed to evaluate proximal and distal reflux burden in patients with extra-esophageal reflux symptoms in particular. Proximal AET has poor sensitivity and reproducibility  and cannot predict symptoms severity. Furthermore, there is no consensus on pH criteria for defining pathologic reflux at the proximal esophagus.[84, 85] Thus, there is no clear evidence that dual probe pH monitoring is of additional value above distal pH probe measurement alone.
6. Interpreting pH-impedance monitoring
6.1. Thresholds to define pathological pH-impedance monitoring
Standardized interpretation of impedance-pH measurement data are based on published normal values.[67-69, 86] Similar AET thresholds are used for impedance-pH monitoring as for pH monitoring alone () and the same thresholds are used when impedance-pH monitoring is performed off or on therapy ( ) [86, 87] (Figure 2).
Published thresholds for abnormal number of reflux episodes during impedance-pH monitoring are quite heterogeneous and outcome data providing their usefulness in GERD management are scant. Given the fairly good reproducibility of this impedance parameter and the preliminary data correlating symptom remission with the decreasing number of reflux episodes in the post-surgical setting, a clearly high number of reflux episodes (above 80) might be considered abnormal () [32-34, 89] while a number of reflux episodes on impedance-pH of 40 or fewer are considered as normal ( ). However, number of reflux episodes alone is not predictive of treatment outcome.[33, 38, 40] Therefore, caution should be adopted to diagnose GERD based on numbers of reflux events alone, and additional clinical and investigation findings should be considered ( ). Consequently, the consensus group recommends reporting number of reflux episodes detected on impedance as an adjunctive tool rather than a primary indicator of abnormal reflux burden.
6.2. Analysis of pH-impedance monitoring
Recommendations are described in Table 4. After completion of the impedance-pH study, data are analyzed using proprietary software and interpreted by the reporting physician. The software identifies individual reflux and swallow events, measures symptom-reflux association, and distinguishes changes in impedance that are not clinically important. Automated analysis is adequate for acid reflux events, but overestimates non-acidic or weakly acidic events. As a consequence, calculation of Symptom Index (SI) and Symptom Association Probability (SAP) might be affected.[92, 93] A manual review of the 2 minutes preceding each symptom event in pH impedance studies may classify most of the patients similarly as manual analysis of the 24-hours study regarding the positivity of SI and SAP. Therefore, manual editing of the 2 minutes preceding each symptom event is recommended ().
6.3. Baseline impedance
Low baseline esophageal impedance is observed in case of impaired esophageal mucosal integrity (erosive esophagitis, Barrett's esophagus, eosinophilic esophagitis) and in case of bolus stasis secondary to severe esophageal motility disorders such as achalasia, absent peristalsis, severe ineffective esophageal motility).[2, 16, 95, 96] Low baseline impedance value (<500 ohms) may affect the sensitivity of reflux recognition during pH-impedance monitoring. While it does not preclude the recognition of reflux during visual analysis, it can make automated recognition difficult () and a manual analysis with magnification of the tracings may help in reflux episodes identification. Furthermore, as low baseline impedance might suggest an additional esophageal process and/or disease, it should be reported in impedance studies.
Recently, different studies suggested that measurement of mucosal esophageal impedance could be useful in the evaluation of patients with suspected GERD. Patients with erosive and non-erosive GERD have lower average baseline impedance values than healthy subjects and patient with functional heartburn.[97-99] Some authors proposed a simplified method to measure baseline impedance. This measurement called mean nocturnal baseline impedance (MNBI) consist of measuring baseline impedance 3 or 5 cm above the LES during the overnight rest as the mean baseline impedance of three 10-minute time periods in a period without swallowing. MNBI was lower in suspected GERD patients with typical symptoms who responded to PPI therapy or anti-reflux surgery compared to those who did not respond.[100-104] Interestingly, the threshold values for abnormal impedance baseline values (<2100 ohms) were quite similar to those obtained by means of an impedance catheter introduced in the working channel of an endoscope. Finally, recent studies found that impedance changes due to acute esophageal inflammation might be reversed with mucosal healing or gastro-esophageal reflux inhibition supporting a role of mucosal impedance as a hallmark of pathological reflux disease.[106, 107]
Since baseline impedance is deemed to have potential as a metric for predicting outcome (), the consensus recommends reporting of MNBI as an exploratory tool, and evaluating its yield over AET and symptom association in large prospective studies with outcome data.
6.4 Post-reflux swallow induced peristaltic wave
Evaluating the efficacy of esophageal chemical clearance might be considered to further characterize GERD. Using 24 hours pH-impedance monitoring, post-reflux swallow induced peristaltic wave (PSPW) index was proposed to evaluate chemical clearance. Briefly PSPW is defined as an antegrade 50% drop in impedance relative to the pre-swallow baseline originating in the most proximal impedance sites, reaching all the distal impedance sites, and followed by at least 50% return to the baseline in all the distal impedance sites (bolus exit). Further PSPW index is calculated manually as the number of refluxes followed within 30 seconds by a PSPW divided by the number of total reflux. PSPW index is significantly lower in patients with reflux esophagitis and NERD compared to controls and patients with functional heartburn.[109, 110] While PSPW index may have complementary value, particularly when pH-impedance is performed on PPI ( ), there is currently not enough evidence for its clinical use.
7. Pharyngeal pH-(impedance) monitoring
The role of pharyngeal reflux monitoring for the diagnosis of gastro-esophageal reflux episodes extending to the pharynx remains unclear. There is no consensus regarding definition of pharyngeal reflux  and important limitations (inaccurate catheter position, artifacts, poor reproducibility).[86, 112-117] Measuring aerosolized pharyngeal acid reflux was proposed but considerable disagreement in the detection of reflux between pharyngeal acid aerosol monitoring and impedance was observed.[118, 119] Thus, measurement of airway and pharyngeal pH cannot be recommended to diagnose gastro-esophageal reflux episodes extending to the pharynx ().[120, 121]
8. Symptom reflux association
Symptom reporting during ambulatory 24-hours reflux monitoring allows investigation of the temporal relationship between reflux and symptom. In this consensus document, the expert group agreed to use the termsand . Recommendations are presented in Table 5.
Recommendations to assess reflux-symptom association
Only symptoms that can reasonably be related to reflux episodes such as cough, chest pain, heartburn, and regurgitation are considered for symptom reflux association analysis, whereas symptoms that are definitely not reflux related are not considered (e.g. headache). It is also not possible to perform reliable symptom reflux association analysis for symptoms that lack a crisp onset and are chronically present, such as dyspnea or hoarseness. As far as possible, the dominant symptom or the most bothersome symptom should be used for symptom reflux association (). It is acceptable to perform separate symptom reflux association testing for a secondary symptom ( ). When the dominant symptom is cough, adding a cough detector (for example catheter with ambulatory pressure sensors to the pH-impedance catheter) can be helpful to identify the exact timing of the cough events and makes it possible to distinguish a cough-reflux sequence from reflux-cough ( ).
The outcome of symptoms reflux association is more reliable when the patient has reported multiple symptom events (at least three per symptom should be reported for a reliable reflux-symptom association analysis). Therefore, patients should be encouraged to induce many symptoms and report them all. Measurement off PPI usually results in a higher number of symptoms reported as well, and therefore provide a higher chance of performing adequate symptom reflux association analysis. There is no upper threshold for number of symptoms allowed. Symptom reflux association is reported for the entire duration of the pH-(impedance) study, and is not broken down by upright or recumbent periods (). The time window for symptoms following a reflux episode is 2 minutes ( ).
When pH testing is used, only pH drops below 4 are used to designate reflux episodes, and drops of 1 pH unit not reaching the threshold of pH 4 do not constitute a reflux episode (). When pH impedance testing is used for symptom reflux association, all reflux events detected by impedance are used in calculation of reflux episodes ( ).
In case of few symptom events and few reflux episodes, analysis can be done by quick overview, but in the majority of cases, a quantitative expression of the strength of the relation between symptom events and reflux episodes is needed. This can be done using the symptom-reflux association parameters, Symptom Index (SI) and Symptom Association Probability (SAP). The Symptom Sensitivity Index (SSI) has limited added value to SI and SAP and is not further discussed.[124-126] The Binomial Symptom Index (BSI) (also named Ghillebert Probability Estimate, GPE) is a statistical formula that can express the probability that symptom events and reflux episodes are related. The BSI and SAP are very strongly related and both could be used interchangeably.
The SI is defined as the percentage of symptom events that are related to reflux episodes, thus number of reflux related symptom events divided by total number of symptom events times 100%. The most often used cut-off is 50%, which means that above 50% the SI is considered positive, i.e. a large proportion of the patient's symptoms are considered to be reflux-related.
The SAP is a statistical parameter that expresses the strength of the relationship between symptom events and reflux episodes during the measurement. The calculation is more complex than the SI and cannot be done manually but is calculated instead by the measurement software. The cut-off for the SAP is 95%, and a SAP above 95% (corresponding to<.05, applying Fisher's exact test on a 2×2 table) is considered positive for a relationship between symptom events and reflux episodes.
SI and SAP have a predictive value for the effect of medical and surgical treatment of reflux disease, and this is independent of acid exposure time ().[40, 129, 130] The result of symptom reflux association analysis has a high degree of reproducibility when repeated, at least as high as the result of the acid exposure time. These indices have some limitations, especially related to day-to-day variability of reflux burden and occurrence of symptom events during the monitoring day. Further only a minority of symptoms is associated with reflux episodes. The SI and SAP are complementary and cannot be directly compared to each other ( ) as they measure different things. The presence of positive SI and positive SAP together provides the best evidence of a clinically relevant association between reflux events and symptoms ( ). If one test is positive and the other is negative, this represents a gray area and further interpretation with other parameters (AET, number of reflux episodes, baseline impedance…) and clinical factors are necessary.
9. GERD diagnosis: defining different phenotypes
Three key questions require consideration when defining GERD phenotypes: (i) Is there evidence of GERD as indicated by esophageal mucosal lesion or increased reflux burden; (ii) Is there an association between reflux episodes and symptom events; and, (iii) Are there non-GERD disorders, (behavioral or functional disorders) that could explain the symptoms?
9.1. Esophageal mucosal lesion and mucosal integrity
Los Angeles grade C or D esophagitis provides robust evidence of GERD, and also predicts the response to treatment.[135-137] Grade A alone is not sufficient for the diagnosis of GERD as it may be encountered in asymptomatic controls. While anti-secretory therapy is frequently prescribed to patients with Grade B esophagitis, caution is advised in referring patients to surgery based solely on Grade B esophagitis. Indeed grade B esophagitis might be encountered in asymptomatic controls. Further progression from grade A/B esophagitis to grade C/D and Barrett's esophagus is observed in 1% to 6% and 1% to 12%, respectively, while it may regress to normal endoscopy in 20% to 60%. Thus, grade B esophagitis is not sufficient to unambivalently proof that a subject symptoms are caused by GERD. Other endoscopic findings such as peptic stricture and Barrett's esophagus >1 cm are indicative of pathological GERD.
Most of patients with GERD symptoms have normal appearing mucosa on endoscopy, and examination of biopsies through conventional histology has shown limited value (i.e., low specificity) in documenting GERD.[141, 142] The latest Rome classification stated that the exclusion of eosinophilic esophagitis (by performing esophageal biopsies) was required to diagnose esophageal functional disorders to perform esophageal biopsies to exclude eosinophilic esophagitis. However, there is limited data regarding the clinical utility of this approach as the majority of patients with eosinophilic esophagitis had endoscopic abnormalities and/or dysphagia.
9.2. Measures of reflux burden
A challenging scenario is encountered when patients have symptoms suggestive of GERD, but normal endoscopy, and incomplete response to acid suppression. In these patients, ambulatory reflux monitoring is useful to define GERD phenotypes and to guide treatment, particularly in patients with PPI-refractory symptoms.[29, 143]
In this consensus, we consider that AET greater than 6% during ambulatory pH-(impedance) monitoring establishes the diagnosis of GERD. The total number of reflux episodes alone and baseline impedance is not sufficient to confirm the diagnosis of GERD and it should be considered as an exploratory tool.
9.3. Measures of association between reflux and symptoms
A positive SI and/or SAP support an association between reflux episodes and symptom events, which is an independent predictor of response to treatment in retrospective, uncontrolled, studies. In patients without evidence of pathological GERD (i.e., normal endoscopy, normal AET, normal number of reflux episodes), a positive symptom association study for heartburn or regurgitation suggests reflux hypersensitivity as defined by Rome IV criteria.
9.4. Non-GERD functional and behavioral disorders
In some patients with symptoms but completely normal evaluation, symptoms may be due to a functional gastro-intestinal disorder such as functional heartburn or functional chest pain. Behavioral disorders such as rumination or supragastric belching might also explain symptoms.[10, 48, 49] While these disorders are not part of the GERD spectrum, they might be encountered in patients with symptoms suggestive of GERD, especially those who are refractory to PPI. An overlap might also exist between GERD and a functional or behavioral disorder.
9.5. Algorithmic approach to GERD phenotypes
GERD definition is based on presence of GERD symptoms, endoscopic findings and results of pH-(impedance) monitoring. Figure 3 summarizes GERD phenotypes. However, there are some borderline cases in which the diagnosis of GERD remains uncertain (grade A and B esophagitis, AET between 4% and 6%). Adding testing such as total number of reflux episodes, baseline impedance, histological evaluation, or evaluation of microscopic esophagitis might be considered to determine if there is other argument in favor of GERD in these patients.[144-146] An alternative approach to phenotype GERD might be to consider GERD mechanisms and high resolution manometry metrics as presented in the accompanying article on motor findings in GERD (Gyawali et al, unpublished data). Finally, where there is a strong suspicion of GERD, repeating a study could also be considered as a negative result might be secondary to intermittent symptoms and day to day variability.[70, 71]
Figure 3. Gastro-esophageal reflux disease phenotypes off and on medication
Reflux monitoring can have a decisive role in the management of patients with symptoms suggestive of GERD. In combination with upper GI endoscopy, it is useful to establish the diagnosis of GERD and to define different phenotypes that may guide the treatment. The working group proposes a definition of pathological GERD. New concepts here are the introduction of areas of uncertain diagnosis (grade A and B esophagitis and AET between 4% and 6%) and exploratory tools for research (total number of reflux episodes, mean nocturnal baseline impedance). Based on GRADE category, the level of evidence is usually very low to moderate and most recommendations rely on expert consensus. Future research might be focused on outcome data to determine if GERD phenotypes are useful in the management of patients with GERD symptoms.
Guarantor of the manuscript: Sabine Roman. The consensus process was supported by the Working Group for Gastrointestinal Motility and Function. This group received an educational grant of United European Gastroenterology (UEG).
SR has served as consultant for Sandhill Scientific and Medtronic. CPG has served as a consultant for Medtronic and Torax, and has received research funding from Medtronic. ES has served as consultant for Medtronic, Abbvie, Takeda, Otsuka, Malesci. RY none. FZ Consultant Allergan, Reckitt Benckiser, Research funding: Medtronic, Sandhill Scientific. JW none to declare. MV Consultant: Medtronic, Torax, Sandhill Scientific. RTu none to declare. RTa none. DS has received research grants from Sandhill Scientific and Reckkit Benckiser. JK has served as a consultant for Medtronic and for Standard Instruments, and has received research funding. MF Consultant and speaker: Given Imaging, Reckitt Benckiser and Shire Pharmaceuticals. Research funding: Given Imaging, Mui Scientific, Reckitt Benckiser, Astra Zeneca and Nestle. Educational activities: Given Imaging, Sandhill Scientific Instruments and Medical Measurement Systems. JEP has as consultant and speaker for Medtonic and Sndhill, as speaker for Takeda and Astra Zeneca and as consultant for Ironwook and Impleo. AJB has served as a consultant for Medical Measurement Systems and has received research funding from Medtronic and Medical Measurement Systems.
SR, CPG, ES, JEP, and AJB study design, manuscript drafting, literature search, critical review of content, approval of final manuscript; RY, FZ, JW, MV, RTu, RTa, DS, JK, and MF literature search, critical review of content, approval of final manuscript; GERD consensus group: critical review of content, approval of final manuscript.
1. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal definition andclassification of gastroesophageal reflux disease: a global evidence-basedconsensus. Am J Gastroenterol. 2006;101:1900-1920; quiz 1943.
3. Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004;328:1490.
5. Sifrim D, Zerbib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut. 2012;61:1340-1354.
6. Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut. 2009;58:295-309.
7. Jobe BA, Richter JE, Hoppo T, et al. Preoperative diagnostic workup before antireflux surgery: an evidence and experience-based consensus of the Esophageal Diagnostic Advisory Panel. J Am Coll Surg. 2013;217:586-597.
9. Zerbib F, Sifrim D, Tutuian R, Attwood S, Lundell L. Modern medical and surgical management of difficult-to-treat GORD. United European Gastroenterol J. 2013;1:21-31.
10. Kessing BF, Bredenoord AJ, Smout AJ. The pathophysiology, diagnosis and treatment of excessive belching symptoms. Am J Gastroenterol 2014;109:1196-1203; (Quiz) 1204.
11. Kessing BF, Smout AJ, Bredenoord AJ. Current diagnosis and management of the rumination syndrome. J Clin Gastroenterol. 2014;48:478-483.
12. Zentilin P, Dulbecco P, Savarino E, Giannini E, Savarino V. Combined multichannel intraluminal impedance and pH-metry: a novel technique to improve detection of gastro-oesophageal reflux literature review. Dig Liver Dis. 2004;36:565-569.
13. Aanen MC, Bredenoord AJ, Samsom M, Smout AJ. Reliability of oesophageal pH recording for the detection of gastro-oesophageal reflux. Scand J Gastroenterol. 2008;43:1442-1447.
14. Vela MF, Tutuian R, Katz PO, Castell DO. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther. 2003;17:243-251.
15. Zerbib F, Roman S, Ropert A, et al. Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol. 2006;101:1956-1963.
16. Savarino E, Zentilin P, Frazzoni M, et al. Characteristics of gastro-esophageal reflux episodes in Barrett's esophagus, erosive esophagitis and healthy volunteers. Neurogastroenterol Motil. 2010;22:1061-e1280.
17. Bredenoord AJ, Weusten BL, Timmer R, Conchillo JM, Smout AJ. Addition of esophageal impedance monitoring to pH monitoring increases the yield of symptom association analysis in patients off PPI therapy. Am J Gastroenterol. 2006;101:453-459.
18. Savarino E, Marabotto E, Zentilin P, et al. The added value of impedance-pH monitoring to Rome III criteria in distinguishing functional heartburn from non-erosive reflux disease. Dig Liver Dis. 2011;43:542-547.
19. Pandolfino JE, Vela MF. Esophageal-reflux monitoring. Gastrointest Endosc 2009;69:917-930.
20. Wong WM, Bautista J, Dekel R, et al. Feasibility and tolerability of transnasal/per-oral placement of the wireless pH capsule vs. traditional 24-h oesophageal pH monitoring – a randomized trial. Aliment Pharmacol Ther. 2005;21:155-163.
21. Sweis R, Fox M, Anggiansah R, et al. Patient acceptance and clinical impact of Bravo monitoring in patients with previous failed catheter-based studies. Aliment Pharmacol Ther. 2009;29:669-676.
22. Pandolfino JE, Richter JE, Ours T, Guardino JM, Chapman J, Kahrilas PJ. Ambulatory esophageal pH monitoring using a wireless system. Am J Gastroenterol. 2003;98:740-749.
23. Penagini R, Sweis R, Mauro A, Domingues G, Vales A, Sifrim D. Inconsistency in the Diagnosis of Functional Heartburn: usefulness of Prolonged Wireless pH Monitoring in Patients With Proton Pump Inhibitor Refractory Gastroesophageal Reflux Disease. J Neurogastroenterol Motil. 2015;21:265-272.
24. Sweis R, Fox M, Anggiansah A, Wong T. Prolonged, wireless pH-studies have a high diagnostic yield in patients with reflux symptoms and negative 24-h catheter-based pH-studies. Neurogastroenterol Motil. 2011;23:419-426.
25. Prakash C, Clouse RE. Wireless pH monitoring in patients with non-cardiac chest pain. Am J Gastroenterol. 2006;101:446-452.
26. Prakash C, Clouse RE. Value of extended recording time with wireless pH monitoring in evaluating gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2005;3:329-334.
27. Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring. Gut. 2006;55:1398-1402.
28. Becker V, Bajbouj M, Waller K, Schmid RM, Meining A. Clinical trial: persistent gastro-oesophageal reflux symptoms despite standard therapy with proton pump inhibitors - a follow-up study of intraluminal-impedance guided therapy. Aliment Pharmacol Ther. 2007;26:1355-1360.
29. Savarino E, Zentilin P, Tutuian R, et al. The role of nonacid reflux in NERD: lessons learned from impedance-pH monitoring in 150 patients off therapy. Am J Gastroenterol. 2008;103:2685-2693.
30. Savarino E, Tutuian R, Zentilin P, et al. Characteristics of reflux episodes and symptom association in patients with erosive esophagitis and nonerosive reflux disease: study using combined impedance-pH off therapy. Am J Gastroenterol. 2010;105:1053-1061.
31. Savarino E, Pohl D, Zentilin P, et al. Functional heartburn has more in common with functional dyspepsia than with non-erosive reflux disease. Gut. 2009;58:1185-1191.
32. Broeders JA, Bredenoord AJ, Hazebroek EJ, Broeders IA, Gooszen HG, Smout AJ. Effects of anti-reflux surgery on weakly acidic reflux and belching. Gut. 2011;60:435-441.
33. Desjardin M, Luc G, Collet D, Zerbib F. 24-hour pH-impedance monitoring ontherapy to select patients with refractory reflux symptoms for antirefluxsurgery. A single center retrospective study. Neurogastroenterol Motil.2016;28:146-152.
34. Frazzoni M, Piccoli M, Conigliaro R, Manta R, Frazzoni L, Melotti G. Refractory gastroesophageal reflux disease as diagnosed by impedance-pH monitoring can be cured by laparoscopic fundoplication. Surg Endosc. 2013;27:2940-2946.
35. Mainie I, Tutuian R, Agrawal A, Adams D, Castell DO. Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen fundoplication. Br J Surg. 2006;93:1483-1487.
36. del Genio G, Tolone S, del Genio F, et al. Prospective assessment of patient selection for antireflux surgery by combined multichannel intraluminal impedance pH monitoring. J Gastrointest Surg. 2008;12:1491-1496.
37. Frazzoni M, Conigliaro R, Melotti G. Reflux parameters as modified by laparoscopic fundoplication in 40 patients with heartburn/regurgitation persisting despite PPI therapy: a study using impedance-pH monitoring. Dig Dis Sci. 2011;56:1099-1106.
39. Francis DO, Goutte M, Slaughter JC, et al. Traditional reflux parameters and not impedance monitoring predict outcome after fundoplication in extraesophageal reflux. Laryngoscope. 2011;121:1902-1909.
40. Patel A, Sayuk GS, Gyawali CP. Acid-based parameters on pH-impedance testing predict symptom improvement with medical management better than impedance parameters. Am J Gastroenterol. 2014;109:836-844.
41. Roman S, Poncet G, Serraj I, Zerbib F, Boulez J, Mion F. Characterization of reflux events after fundoplication using combined impedance-pH recording. Br J Surg. 2007;94:48-52.
42. Kessing BF, Broeders JA, Vinke N, et al. Gas-related symptoms after antireflux surgery. Surg Endosc. 2013;27:3739-3747.
43. Sifrim D, Dupont L, Blondeau K, Zhang X, Tack J, Janssens J. Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring. Gut. 2005;54:449-454.
44. Blondeau K, Dupont LJ, Mertens V, Tack J, Sifrim D. Improved diagnosis of gastro-oesophageal reflux in patients with unexplained chronic cough. Aliment Pharmacol Ther. 2007;25:723-732.
45. Tutuian R, Mainie I, Agrawal A, Adams D, Castell DO. Nonacid reflux in patients with chronic cough on acid-suppressive therapy. Chest. 2006;130:386-391.
46. Patterson N, Mainie I, Rafferty G, et al. Nonacid reflux episodes reaching the pharynx are important factors associated with cough. J Clin Gastroenterol. 2009;43:414-419.
47. Ribolsi M, Savarino E, De Bortoli N, et al. Reflux pattern and role of impedance-pH variables in predicting PPI response in patients with suspected GERD-related chronic cough. Aliment Pharmacol Ther. 2014;40:966-973.
48. Hemmink GJ, Ten Cate L, Bredenoord AJ, Timmer R, Weusten BL, Smout AJ. Speech therapy in patients with excessive supragastric belching–a pilot study. Neurogastroenterol Motil. 2010;22(24–28):e22-e23.
49. Kessing BF, Bredenoord AJ, Smout AJ. Objective manometric criteria for the rumination syndrome. Am J Gastroenterol. 2014;109:52-59.
50. Tucker E, Knowles K, Wright J, Fox MR. Rumination variations: aetiology and classification of abnormal behavioural responses to digestive symptoms based on high-resolution manometry studies. Aliment Pharmacol Ther. 2013;37:263-274.
51. Richter JE, Pandolfino JE, Vela MF, et al. Utilization of wireless pH monitoring technologies: a summary of the proceedings from the esophageal diagnostic working group. Dis Esophagus. 2013;26:755-765.
52. Aksglaede K, Funch-Jensen P, Thommesen P. Intra-esophageal pH probe movement during eating and talking. A videoradiographic study. Acta Radiol. 2003;44:131-135.
53. Pandolfino JE, Schreiner MA, Lee TJ, Zhang Q, Boniquit C, Kahrilas PJ. Comparison of the Bravo wireless and Digitrapper catheter-based pH monitoring systems for measuring esophageal acid exposure. Am J Gastroenterol. 2005;100:1466-1476.
54. Kahrilas PJ, Quigley EM. Clinical esophageal pH recording: a technical review for practice guideline development. Gastroenterology. 1996;110:1982-1996.
55. Johnsson F, Joelsson B, Isberg PE. Ambulatory 24 hour intraesophageal pH-monitoring in the diagnosis of gastroesophageal reflux disease. Gut. 1987;28:1145-1150.
56. Johnson LF, DeMeester TR. Development of the 24-hour intraesophageal pH monitoring composite scoring system. J Clin Gastroenterol. 1986;8(Suppl 1):52-58.
57. Wiener GJ, Morgan TM, Copper JB, et al. Ambulatory 24-hour esophageal pH monitoring. Reproducibility and variability of pH parameters. Dig Dis Sci. 1988;33:1127-1133.
58. Schindlbeck NE, Heinrich C, Konig A, Dendorfer A, Pace F, Muller-Lissner SA. Optimal thresholds, sensitivity, and specificity of long-term pH-metry for the detection of gastroesophageal reflux disease. Gastroenterology. 1987;93:85-90.
59. Wang AJ, Wang H, Xu L, et al. Predictors of clinical response of acid suppression in Chinese patients with gastroesophageal reflux disease. Dig Liver Dis. 2013;45:296-300.
60. de Bortoli N, Martinucci I, Savarino E, et al. Proton pump inhibitor responders who are not confirmed as GERD patients with impedance and pH monitoring: who are they? Neurogastroenterol Motil. 2014;26:28-35.
61. Vitale GC, Cheadle WG, Sadek S, Michel ME, Cuschieri A. Computerized 24-hour ambulatory esophageal pH monitoring and esophagogastroduodenoscopy in the reflux patient. A comparative study.. Ann Surg. 1984;200:724-728.
62. Mattioli S, Pilotti V, Spangaro M, et al. Reliability of 24-hour home esophageal pH monitoring in diagnosis of gastroesophageal reflux. Dig Dis Sci. 1989;34:71-78.
63. Smout AJ, Breedijk M, van der Zouw C, Akkermans LM. Physiological gastroesophageal reflux and esophageal motor activity studied with a new system for 24-hour recording and automated analysis. Dig Dis Sci. 1989;34:372-378.
64. Masclee AA, de Best AC, de Graaf R, Cluysenaer OJ, Jansen JB. Ambulatory 24-hour pH-metry in the diagnosis of gastroesophageal reflux disease. Determination of criteria and relation to endoscopy. Scand J Gastroenterol 1990;25:225-230.
65. Richter JE, Bradley LA, DeMeester TR, Wu WC. Normal 24-hr ambulatory esophageal pH values. Influence of study center, pH electrode, age, and gender. Dig Dis Sci. 1992;37:849-856.
66. Kasapidis P, Xynos E, Mantides A, et al. Differences in manometry and 24-Hambulatory pH-metry between patients with and without endoscopic orhistological esophagitis in gastroesophageal reflux disease. Am JGastroenterol. 1993;88:1893-1899.
67. Zentilin P, Iiritano E, Dulbecco P, et al. Normal values of 24-h ambulatory intraluminal impedance combined with pH-metry in subjects eating a Mediterranean diet. Dig Liver Dis. 2006;38:226-232.
68. Shay S, Tutuian R, Sifrim D, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol. 2004;99:1037-1043.
69. Zerbib F, des Varannes SB, Roman S, et al. Normal values and day-to-day variability of 24-h ambulatory oesophageal impedance-pH monitoring in a Belgian-French cohort of healthy subjects. Aliment Pharmacol Ther 2005;22:1011-1021.
70. Johnsson F, Joelsson B. Reproducibility of ambulatory oesophageal pH monitoring. Gut. 1988;29:886-889.
71. Scarpulla G, Camilleri S, Galante P, Manganaro M, Fox M. The impact of prolonged pH measurements on the diagnosis of gastroesophageal reflux disease: 4-day wireless pH studies. Am J Gastroenterol. 2007;102:2642-2647.
72. Ayazi S, Lipham JC, Portale G, et al. Bravo catheter-free pH monitoring: normal values, concordance, optimal diagnostic thresholds, and accuracy. Clin Gastroenterol Hepatol. 2009;7:60-67.
73. Wenner J, Johnsson F, Johansson J, Oberg S. Wireless oesophageal pH monitoring: feasibility, safety and normal values in healthy subjects. Scand J Gastroenterol. 2005;40:768-774.
74. Dickman R, Green C, Fass SS, et al. Relationships between sleep quality and pH monitoring findings in persons with gastroesophageal reflux disease. J Clin Sleep Med. 2007;3:505-513.
75. Frazzoni M, De Micheli E, Savarino V. Different patterns of oesophageal acid exposure distinguish complicated reflux disease from either erosive reflux oesophagitis or non-erosive reflux disease. Aliment Pharmacol Ther. 2003;18:1091-1098.
76. Orr WC, Allen ML, Robinson M. The pattern of nocturnal and diurnal esophageal acid exposure in the pathogenesis of erosive mucosal damage. Am J Gastroenterol. 1994;89:509-512.
77. Burgerhart JS, van de Meeberg PC, Siersema PD, Smout AJ. Nocturnal and daytime esophageal acid exposure in normal-weight, overweight, and obese patients with reflux symptoms. Eur J Gastroenterol Hepatol. 2014;26:6-10.
78. Piesman M, Hwang I, Maydonovitch C, Wong RK. Nocturnal reflux episodes following the administration of a standardized meal. Does timing matter? Am J Gastroenterol. 2007;102:2128-2134.
79. Broeders JA, Draaisma WA, Bredenoord AJ, et al. Oesophageal acid hypersensitivity is not a contraindication to Nissen fundoplication. Br J Surg. 2009;96:1023-1030.
80. Wayman J, Myers JC, Jamieson GG. Preoperative gastric emptying and patterns of reflux as predictors of outcome after laparoscopic fundoplication. Br J Surg. 2007;94:592-598.
81. Hong D, Swanstrom LL, Khajanchee YS, Pereira N, Hansen PD. Postoperative objective outcomes for upright, supine, and bipositional reflux disease following laparoscopic nissen fundoplication. Arch Surg 2004;139:848-852; discussion 852-844.
82. Vaezi MF, Schroeder PL, Richter JE. Reproducibility of proximal probe pH parameters in 24-hour ambulatory esophageal pH monitoring. Am J Gastroenterol. 1997;92:825-829.
83. Noordzij JP, Khidr A, Desper E, Meek RB, Reibel JF, Levine PA. Correlation of pH probe-measured laryngopharyngeal reflux with symptoms and signs of reflux laryngitis. Laryngoscope. 2002;112:2192-2195.
84. Ayazi S, Hagen JA, Zehetner J, et al. Proximal esophageal pH monitoring: improved definition of normal values and determination of a composite pH score. J Am Coll Surg. 2010;210:345-350.
85. Reichel O, Issing WJ. Impact of different pH thresholds for 24-hour dual probe pH monitoring in patients with suspected laryngopharyngeal reflux. J Laryngol Otol. 2008;122:485-489.
86. Zerbib F, Roman S, Bruley Des Varannes S, et al. Normal values of pharyngeal and esophageal 24-hour pH impedance in individuals on and off therapy and interobserver reproducibility. Clin Gastroenterol Hepatol. 2013;11:366-372.
87. Tutuian R, Mainie I, Agrawal A, Freeman J, Castell DO. Normal values for ambulatory 24-h combined impedance pH-monitoring on acid suppressive therapy. Gastroenterology. 2006;130:A171.
88. Savarino E, de Bortoli N, Furnari M, et al. Different Accuracy of Various Impedance-pH Normal Values in Diagnosing GERD in Patients with Proven or Highly Suspected Reflux Disease. Dig Liver Dis. 2014;46:S8.
89. Savarino E, Marabotto E, Salvador R, et al. Patients with non-acid reflux disease and those with erosive and non-erosive reflux disease have similar response to anti-reflux surgical therapy. Gastroenterology 2015;148:S-611.
90. Furnari M, Tolone S, Savarino E. Caution about overinterpretation of number of reflux episodes in reflux monitoring for refractory gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2016;14:1040.
91. Blondeau K, Tack J. Pro: impedance testing is useful in the management of GERD. Am J Gastroenterol. 2009;104:2664-2666.
92. Roman S, Bruley des Varannes S, Pouderoux P, et al. Ambulatory 24-h oesophageal impedance-pH recordings: reliability of automatic analysis for gastro-oesophageal reflux assessment. Neurogastroenterol Motil 2006;18:978-986.
93. Hemmink GJ, Bredenoord AJ, Aanen MC, Weusten BL, Timmer R, Smout AJ. Computer analysis of 24-h esophageal impedance signals. Scand J Gastroenterol. 2011;46:271-276.
94. Tenca A, Campagnola P, Bravi I, Benini L, Sifrim D, Penagini R. Impedance pH Monitoring: intra-observer and Inter-observer Agreement and Usefulness of a Rapid Analysis of Symptom Reflux Association. J Neurogastroenterol Motil. 2014;20:205-211.
95. van Rhijn BD, Kessing BF, Smout AJ, Bredenoord AJ. Oesophageal baseline impedance values are decreased in patients with eosinophilic oesophagitis. United European Gastroenterol J. 2013;1:242-248.
96. Savarino E, Gemignani L, Pohl D, et al. Oesophageal motility and bolus transit abnormalities increase in parallel with the severity of gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2011;34:476-486.
97. Farre R, Blondeau K, Clement D, et al. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut. 2011;60:885-892.
99. Woodland P, Al-Zinaty M, Yazaki E, Sifrim D. In vivo evaluation of acid-induced changes in oesophageal mucosa integrity and sensitivity in non-erosive reflux disease. Gut. 2013;62:1256-1261.
100. Martinucci I, de Bortoli N, Savarino E, et al. Esophageal baseline impedancelevels in patients with pathophysiological characteristics of functionalheartburn. Neurogastroenterol Motil. 2014;26:546-555.
101. de Bortoli N, Martinucci I, Savarino E, et al. Association between baseline impedance values and response proton pump inhibitors in patients with heartburn. Clin Gastroenterol Hepatol. 2015;13(1082–1088):e1081.
102. Kandulski A, Weigt J, Caro C, Jechorek D, Wex T, Malfertheiner P. Esophagealintraluminal baseline impedance differentiates gastroesophageal reflux diseasefrom functional heartburn. Clin Gastroenterol Hepatol. 2015;13:1075-1081.
103. Patel A, Wang D, Sainani N, Sayuk GS, Gyawali CP. Distal mean nocturnalbaseline impedance on pH-impedance monitoring predicts reflux burden andsymptomatic outcome in gastro-oesophageal reflux disease. Aliment PharmacolTher. 2016;44:890-898.
104. Frazzoni M, de Bortoli N, Frazzoni L, et al. The added diagnostic value of postreflux swallow-induced peristaltic wave index and nocturnal baseline impedance in refractory reflux disease studied with on-therapy impedance-pH monitoring. Neurogastroenterol Motil 2017;29:e12947.
105. Ates F, Yuksel ES, Higginbotham T, et al. Mucosal impedance discriminates GERD from non-GERD conditions. Gastroenterology. 2015;148:334-343.
106. Rinsma NF, Farre R, Bouvy ND, Masclee AA, Conchillo JM. The effect of endoscopic fundoplication and proton pump inhibitors on baseline impedance and heartburn severity in GERD patients. Neurogastroenterol Motil. 2015;27:220-228.
107. van Rhijn BD, Weijenborg PW, Verheij J, et al. Proton pump inhibitors partially restore mucosal integrity in patients with proton pump inhibitor-responsive esophageal eosinophilia but not eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2014;12(1815–1823):e1812.
108. Frazzoni M, Manta R, Mirante VG, Conigliaro R, Frazzoni L, Melotti G. Esophageal chemical clearance is impaired in gastro-esophageal reflux disease–a 24-h impedance-pH monitoring assessment. Neurogastroenterol Motil. 2013;25(399–406):e295.
109. Frazzoni M, Bertani H, Manta R, et al. Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis. Dig Liver Dis. 2014;46:596-602.
110. Frazzoni M, Savarino E, de Bortoli N, et al. Analyses of the Post-reflux Swallow-induced Peristaltic Wave Index and Nocturnal Baseline Impedance Parameters Increase the Diagnostic Yield of Impedance-pH Monitoring of Patients With Reflux Disease. Clin Gastroenterol Hepatol. 2016;14:40-46.
111. Golub JS, Johns MM 3rd, Lim JH, DelGaudio JM, Klein AM. Comparison of an oropharyngeal pH probe and a standard dual pH probe for diagnosis of laryngopharyngeal reflux. Ann Otol Rhinol Laryngol. 2009;118:1-5.
113. Desjardin M, Roman S, des Varannes SB, et al. Pharyngeal pH alone is not reliable for the detection of pharyngeal reflux events: a study with oesophageal and pharyngeal pH-impedance monitoring. United European Gastroenterol J 2013;1:438-444.
114. Kawamura O, Aslam M, Rittmann T, Hofmann C, Shaker R. Physical and pH properties of gastroesophagopharyngeal refluxate: a 24-hour simultaneous ambulatory impedance and pH monitoring study. Am J Gastroenterol. 2004;99:1000-1010.
115. Oelschlager BK, Quiroga E, Isch JA, Cuenca-Abente F. Gastroesophageal and pharyngeal reflux detection using impedance and 24-hour pH monitoring in asymptomatic subjects: defining the normal environment. J Gastrointest Surg. 2006;10:54-62.
116. Hoppo T, Sanz AF, Nason KS, et al. How much pharyngeal exposure is “normal”? normative data for laryngopharyngeal reflux events using hypopharyngeal multichannel intraluminal impedance (HMII) J Gastrointest Surg 2012;16:16-24.
117. Williams RB, Ali GN, Wallace KL, Wilson JS, De Carle DJ, Cook IJ. Esophagopharyngeal acid regurgitation: dual pH monitoring criteria for its detection and insights into mechanisms. Gastroenterology. 1999;117:1051-1061.
118. Wiener GJ, Tsukashima R, Kelly C, et al. Oropharyngeal pH monitoring for the detection of liquid and aerosolized supraesophageal gastric reflux. J Voice. 2009;23:498-504.
119. Worrell SG, DeMeester SR, Greene CL, Oh DS, Hagen JA. Pharyngeal pH monitoring better predicts a successful outcome for extraesophageal reflux symptoms after antireflux surgery. Surg Endosc. 2013;27:4113-4118.
120. Yadlapati R, Adkins C, Jaiyeola DM, et al. Abilities of Oropharyngeal pH Tests and Salivary Pepsin Analysis to Discriminate Between Asymptomatic Volunteers and Subjects With Symptoms of Laryngeal Irritation. Clin Gastroenterol Hepatol. 2016;14(535–542):e532.
121. Mazzoleni G, Vailati C, Lisma DG, Testoni PA, Passaretti S. Correlation between oropharyngeal pH-monitoring and esophageal pH-impedance monitoring in patients with suspected GERD-related extra-esophageal symptoms. Neurogastroenterol Motil. 2014;26:1557-1564.
122. Hemmink GJ, Bredenoord AJ, Weusten BL, Monkelbaan JF, Timmer R, Smout AJ. Esophageal pH-impedance monitoring in patients with therapy-resistant reflux symptoms: ‘on’ or ‘off’ proton pump inhibitor? Am J Gastroenterol. 2008;103:2446-2453.
125. Weusten BL, Roelofs JM, Akkermans LM, Van Berge-Henegouwen GP, Smout AJ. The symptom-association probability: an improved method for symptom analysis of 24-hour esophageal pH data. Gastroenterology. 1994;107:1741-1745.
126. Breumelhof R, Smout AJ. The symptom sensitivity index: a valuable additional parameter in 24-hour esophageal pH recording. Am J Gastroenterol. 1991;86:160-164.
127. Ghillebert G, Janssens J, Vantrappen G, Nevens F, Piessens J. Ambulatory 24 hour intraoesophageal pH and pressure recordings v provocation tests in the diagnosis of chest pain of oesophageal origin. Gut. 1990;31:738-744.
128. Kushnir VM, Sathyamurthy A, Drapekin J, Gaddam S, Sayuk GS, Gyawali CP. Assessment of concordance of symptom reflux association tests in ambulatory pH monitoring. Aliment Pharmacol Ther. 2012;35:1080-1087.
129. Watson RG, Tham TC, Johnston BT, McDougall NI. Double blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux–the “sensitive oesophagus”. Gut. 1997;40:587-590.
130. Taghavi SA, Ghasedi M, Saberi-Firoozi M, et al. Symptom association probability and symptom sensitivity index: preferable but still suboptimal predictors of response to high dose omeprazole. Gut. 2005;54:1067-1071.
131. Aanen MC, Bredenoord AJ, Numans ME, Samson M, Smout AJ. Reproducibility of symptom association analysis in ambulatory reflux monitoring. Am J Gastroenterol. 2008;103:2200-2208.
132. Slaughter JC, Goutte M, Rymer JA, et al. Caution about overinterpretation of symptom indexes in reflux monitoring for refractory gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2011;9:868-874.
133. Roman S, Keefer L, Imam H, et al. Majority of symptoms in esophageal reflux PPI non-responders are not related to reflux. Neurogastroenterol Motil. 2015;27:1667-1674.
134. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172-180.
135. Vakil NB, Traxler B, Levine D. Dysphagia in patients with erosive esophagitis: prevalence, severity, and response to proton pump inhibitor treatment. Clin Gastroenterol Hepatol. 2004;2:665-668.
136. Khan M, Santana J, Donnellan C, Preston C, Moayyedi P. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev 2007;18:CD003244.
137. Van Pinxteren B, Sigterman KE, Bonis P, Lau J, Numans ME. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev. 2010;11:CD002095.
138. Ronkainen J, Aro P, Storskrubb T, et al. High prevalence of gastroesophageal reflux symptoms and esophagitis with or without symptoms in the general adult Swedish population: a Kalixanda study report. Scand J Gastroenterol. 2005;40:275-285.
139. Savarino E, de Bortoli N, De Cassan C, et al. The natural history of gastro-esophageal reflux disease: a comprehensive review [published online November 9 2016]. Dis Esophagus 2016. doi: https ://doi. org/10.1111/dote.12511.
140. Wang A, Mattek NC, Holub JL, Lieberman DA, Eisen GM. Prevalence of complicated gastroesophageal reflux disease and Barrett's esophagus among racial groups in a multi-center consortium. Dig Dis Sci. 2009;54:964-971.
141. Savarino E, Zentilin P, Mastracci L, et al. Microscopic esophagitis distinguishes patients with non-erosive reflux disease from those with functional heartburn. J Gastroenterol. 2013;48:473-482.
142. Kandulski A, Jechorek D, Caro C, et al. Histomorphological differentiation of non-erosive reflux disease and functional heartburn in patients with PPI-refractory heartburn. Aliment Pharmacol Ther. 2013;38:643-651.
144. Kia L, Pandolfino JE, Kahrilas PJ. Biomarkers of Reflux Disease. Clin Gastroenterol Hepatol. 2016;14:790-797.
145. Vieth M, Mastracci L, Vakil N, et al. Epithelial Thickness is a Marker Gastroesophageal Reflux Disease. Clin Gastroenterol Hepatol. 2016;14:1544-1551.
146. Vieth M, Mastracci L, Vakil N, et al. Epithelial Thickness is a Marker of Gastroesophageal Reflux Disease. Clin Gastroenterol Hepatol. 2016;14(1544–1551):e1541.
147. Gyawali CP, Roman S, Bredenoord AJ, et al. Classification of esophageal motor findings in gastroesophageal reflux disease: conclusions from an international consensus group. Submitted to Neurogastroenterol Motil 2017: in revision.
Назад в раздел
Популярно о болезнях ЖКТ читайте в разделе "Пациентам"
Информация на сайте www.gastroscan.ru предназначена для образовательных и научных целей. Условия использования.