In Focus

Reflux Diagnostics: Modern Techniques and Future Directions


Testing on or off PPI?

For symptoms attributable to GERD that persist despite properly administered PPI therapy, the 2013 American College of Gastroenterology guidelines suggest upper endoscopy with esophageal biopsies for typical symptoms and appropriate referrals for atypical symptoms.24 However, if these evaluations are unremarkable, reflux monitoring is recommended, with PPI status for testing guided by the pre-test probability of GERD: with a low pre-test probability of GERD, reflux testing is best performed off PPI with either pH or combined pH-impedance testing. In contrast, with a high pre-test probability of GERD, testing is best performed on PPI with combined pH-impedance testing. A similar concept is proposed in the Rome IV approach (Figure 2)23 and on GERD consensus guidelines:7 when heartburn or chest pain persists despite PPI therapy and endoscopy and esophageal biopsies are normal, evidence for GERD (past esophagitis, Barrett’s esophagus, peptic stricture, or prior positive reflux testing) prompts pH-impedance monitoring on PPI therapy (i.e., proven GERD). Those without this evidence for proven GERD (i.e., unproven GERD) are best tested off PPI, and the test utilized can be either pH alone or combined pH-impedance.

GERD phenotypes and management

The presence or absence of the two core metrics on ambulatory reflux monitoring – abnormal AET and positive SRA – can stratify symptomatic GERD patients into phenotypes that predict symptomatic improvement with antireflux therapy and guide management of symptoms (Figure 3).25,26 The presence of both abnormal AET and positive SRA suggests “strong” evidence for GERD, for which symptom improvement is likely with maximization of antireflux therapy, which can include BID PPI, baclofen (to decrease transient LES relaxations), alginates (such as Gaviscon), and consideration of endosopic or surgical antireflux procedures such as fundoplication or magnetic sphincter augmentation. Abnormal AET but negative SRA is regarded as “good” evidence for GERD, for which similar antireflux therapies can be advocated. Normal AET but positive SRA is designated as “reflux hypersensitivity,”23 with increasing proportions of patients meeting this phenotype when tested with combined pH-impedance and off PPI therapy.27 Both normal AET and negative SRA suggest equivocal evidence for GERD and the likely presence of a functional esophageal disorder, such as functional heartburn.23 For reflux hypersensitivity and especially functional esophageal disorders, antireflux therapy is unlikely to be as effective and management can include pharmacologic neuromodulation (such as tricyclic antidepressants administered at bedtime) as well as adjunctive nonpharmacologic approaches (such as stress reduction, relaxation, hypnosis, or cognitive-behavioral therapy).

The future of reflux diagnostics

Phenotyping of GERD Based on Distal Esophageal Acid Exposure Time (AET) and Symptom Association Probability (SAP)

Reflux testing, especially 24-hour catheter-based monitoring, offers cross-sectional assessment of reflux burden and does not take day-to-day variations in reflux exposure into account in a disease characterized by chronic symptoms and long-term management implications. This shortcoming has prompted interest in novel reflux diagnostics that may afford further insight into longitudinal reflux exposure. Baseline mucosal impedance, which can be gleaned from pH-impedance tracings during nocturnal resting periods28 or by using prototype devices at endoscopy,29 can segregate erosive and nonerosive GERD from controls and may serve as a surrogate marker for reflux-induced mucosal changes and esophageal mucosal integrity.29-32 Postreflux swallow-induced peristaltic wave index, or the frequencies with which reflux events are followed by clearing esophageal peristaltic waves, represents another novel reflux metric extracted from pH-impedance tracings that may be a marker of refluxate clearance and resolution of esophageal mucosal acidification.33 Finally, there has been revived interest in the value of dilated intercellular spaces on electron microscopy to assess esophageal mucosal integrity to provide evidence of longitudinal – rather than cross-sectional – reflux exposure.34


For esophageal symptoms potentially attributable to GERD that persist despite optimized PPI therapy, esophageal testing should be undertaken, starting with endoscopy and biopsies and proceeding to ambulatory reflux monitoring with HRM. The decisions between pH testing alone versus combined pH-impedance monitoring, and between testing on or off PPI therapy, can be guided either by the pre-test probability of GERD or whether GERD has been proven or unproven in prior evaluations (Figure 2). Elevated AET and positive SRA with impedance-detected reflux events can predict the likelihood of successful management outcomes from antireflux therapy. These two core metrics can be utilized to phenotype GERD and guide management approaches for persisting symptoms (Figure 3). Novel impedance metrics (baseline mucosal impedance, postreflux swallow-induced peristaltic wave index) and markers for esophageal mucosal damage continue to be studied as potential markers for evidence of longitudinal reflux exposure.

Dr. Patel is assistant professor of medicine, division of gastroenterology, Duke University School of Medicine and the Durham Veterans Affairs Medical Center, Durham, N.C. Dr. Gyawali is professor of medicine, division of gastroenterology, Washington University School of Medicine, St. Louis, Mo.

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