C. Prakash Gyawali, MD, MRCP

 

Introduction

Chronic esophageal symptoms attributed to gastroesophageal reflux disease (GERD) are common presenting symptoms in gastroenterology, leading to high healthcare costs and adverse quality of life globally.^1,2 The clinical diagnosis of GERD hinges on the presence of “troublesome” compatible typical symptoms (heartburn, acid regurgitation) or evidence of mucosal injury on endoscopy (esophagitis, Barrett’s esophagus, peptic stricture).³ With the growing availability of proton pump inhibitors (PPIs), patients and clinicians often utilize an empiric therapeutic trial of PPI as an initial test, with symptom improvement in the absence of alarm symptoms indicating a high likelihood of GERD.⁴ A meta-analysis of studies that used objective measures of GERD (in this case, 24-hour pH monitoring) showed that the “PPI test” has a sensitivity of 78%, but a specificity of only 54%, as a diagnostic approach to GERD symptoms.⁵ Apart from noncardiac chest pain, the diagnostic yield is even lower for atypical and extra-esophageal symptoms such as cough or laryngeal symptoms.⁶

Therefore, when symptoms persist despite seemingly adequate PPI therapy, esophageal investigation may start with endoscopy but continues with ambulatory reflux and motility testing.⁷ At endoscopy, exclusion of eosinophilic esophagitis with esophageal biopsies represents an important component of initial evaluation when symptoms are refractory to PPIs.⁸ Further, the more atypical the presentation, the greater the need for esophageal testing prior to long-term PPI therapy. Esophageal function testing is also indicated when confirmation of GERD is needed prior to surgical or endoscopic reflux procedures.
 

The “nuts and bolts” of reflux testing

Ambulatory reflux testing assesses esophageal reflux burden and symptom-reflux association (SRA). Individual reflux events are identified as either a drop in esophageal pH to less than 4 (acid reflux events), or a sharp decrease in esophageal impedance measurements in a retrograde fashion (impedance-detected reflux events), with subsequent recovery to the baseline in each instance. Ambulatory reflux testing affords insight into three areas: 1) measurement of esophageal acid exposure time (AET); the cumulative time duration when distal esophageal pH is less than 4 at the recording site, reported as a percentage of the recording period; 2) measurement of the number of reflux events both acidic (from pH monitoring) and weakly acidic/alkaline (from impedance monitoring); and 3) quantitative evaluation of the association between reported symptom episodes and reflux events.

The three available modalities of ambulatory reflux monitoring consist of catheter-based pH, wireless pH, and combined catheter-based pH-impedance monitoring. Catheter-based pH monitoring, introduced in the 1970s, requires transnasal catheter placement and typically records for 24 hours before catheter removal. The catheter is positioned with the distal pH sensor 5 cm proximal to the upper margin of the manometrically identified lower esophageal sphincter (LES). New guidelines suggest AET less than 4% is reliably normal, while AET greater than 6% is pathologic; values in between are considered borderline and require alternate evidence for GERD, such as endoscopic findings.⁷ Wireless pH probes are placed 6 cm proximal to the squamocolumnar junction at endoscopy and communicate with a pager-sized receiver worn by the patient.⁹ Patient comfort is not compromised, with less restriction of typical patient activities compared to catheter-based testing, facilitating longer recording periods of 48-96 hours, which can overcome day-to-day variations in esophageal reflux burden.⁷ With catheter-based pH-impedance monitoring, multiple pairs of impedance sensors measure the resistance to flow of a tiny electrical current between sensors. Since resistance to flow (that is, impedance) is low in the presence of a bolus or refluxate in the esophageal lumen, the impedance tracing drops during reflux events in a retrograde fashion across the esophageal impedance sensor pairs, regardless of the acidity of the reflux (Figure 1).¹⁰ Combined pH-impedance testing thus detects refluxate in the esophagus regardless of pH, improving the sensitivity of detection of reflux events over pH testing alone, thereby promoting greater yield of SRA. However, there remains wide inter-observer variation on the designation of impedance reflux events.¹¹

The two most commonly utilized SRA metrics are the symptom index (SI) and symptom-association probability (SAP). Individual symptom episodes are designated as related to preceding reflux events if they occur within 2 minutes of the reflux events. The SI represents the simple ratio of the number of reflux-related symptoms to the total number of symptom episodes reported during the ambulatory reflux study, with values above 50% designated as positive.¹² For calculation of the SAP, the ambulatory reflux study is divided into 2-minute intervals. For each interval, the presence or absence of a reflux event and a symptom episode is assessed; the final counts are tabulated on a 2 x 2 table, and a Fisher exact test is applied to generate a “P” value. The SAP is positive if P is less than 0.05, corresponding to an SAP of greater than 95%, or a less than 5% chance that the observed association between symptoms and reflux events occurred by chance.¹³ The SAP can also be calculated post-hoc with data typically extracted during a pH study, using statistical modeling; termed the Ghillebert Probability Estimate,¹⁴ this corresponds well with the former method of SAP calculation.¹⁵

The SI and SAP can be calculated individually for acid-detected reflux events and for impedance-detected reflux events. Since reflux events are better detected with impedance, combined pH-impedance testing increases the yield of detecting positive SRA, especially when performed off PPI therapy.^16,17 Because these indices are heavily reliant on patient reporting of symptom episodes, SRA can be overinterpreted;¹⁸ positive associations are more clinically useful than negative results in the evaluation of symptoms attributed to GERD.¹⁹ Despite these concerns, the two most consistent predictors of symptomatic outcome with antireflux therapy on pH-impedance testing are abnormal AET and positive SAP with impedance-detected reflux events.¹⁷

Copyright Elsevier/AGA

Along with reflux testing, an esophageal high-resolution manometry (HRM) study is typically performed to establish the location of the LES for placement of reflux catheters. Beyond this primary indication, HRM serves the important role of excluding significant esophageal motor disorders in these patients, particularly achalasia spectrum disorders.²⁰ Despite a diametrically opposite pathophysiology compared to GERD, achalasia can present with retrosternal discomfort (often interpreted as heartburn) and esophageal regurgitation (potentially interpreted as acid regurgitation).²¹ Therefore, achalasia spectrum disorders can be mistaken for GERD and managed with acid suppression, thereby contributing to the pool of symptomatic patients refractory to PPI therapy. HRM has high accuracy and specificity for the diagnosis of achalasia and other major esophageal motor disorders.²² Other foregut disorders diagnosed using HRM (typically combined HRM and impedance, or HRiM) include rumination and supragastric belching. The exclusion of a major esophageal motor disorder is also a requirement for the diagnosis of a functional esophageal disorder, where esophageal reflux testing is normal.²³

 

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

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

Conclusions

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.

 

References

1. Shaheen N.J., et al. Am J Gastroenterol. 2006;101:2128-38.

2. Patel A., Gyawali C.P.. Switzerland: Springer International, 2016.

3. Vakil N., et al. Am J Gastroenterol. 2006;101:1900-20; quiz 1943.

4. Fass R., et al. Arch Intern Med. 1999;159:2161-8.

5. Numans M.E., et al. Ann Intern Med. 2004;140:518-27.

6. Shaheen N.J., et al. Aliment Pharmacol Ther. 2011;33:225-34.

7. Roman S., et al. Neurogastroenterol Motil Mar 31. doi: 10.1111/nmo.13067. [Epub ahead of print] 2017.

8. Dellon E.S., et al. Am J Gastroenterol. 2013;108:679-92; quiz 693.

9. Pandolfino JE, Vela MF. Gastrointest Endosc. 2009;69:917-30, 930 e1.

10. Shay S., et al. Am J Gastroenterol. 2004;99:1037-43.

11. Zerbib F., et al. Clin Gastroenterol Hepatol. 2013;11:366-72.

12. Wiener G.J., et al. Am J Gastroenterol 1988;83:358-61.

13. Weusten B.L., et al. Gastroenterology. 1994;107:1741-5.

14. Ghillebert G., et al. Gut 1990;31:738-44.

15. Kushnir V.M., et al. Aliment Pharmacol Ther. 2012;35(9):1080-7.

16. Bredenoord A.J., et al. Am J Gastroenterol. 2006;101:453-9.

17. Patel A., et al. Clin Gastroenterol Hepatol. 2015;13:884-91.

18. Slaughter J.C., et al. Clin Gastroenterol Hepatol. 2011;9:868-74.

19. Kavitt R.T., et al. Am J Gastroenterol. 2012;107:1826-32.

20. Kahrilas P.J., et al. Gastroenterology 2008;135:1383-91, 1391 e1-5.

21. Kessing B.F., et al. Clin Gastroenterol Hepatol. 2011;9:1020-4.

22. Kahrilas P.J., et al. Neurogastroenterol Motil. 2015;27:160-74.

23. Aziz A, et al. Esophageal disorders. Gastroenterology 2016;150:1368-79.

24. Katz P.O., et al. Am J Gastroenterol. 2013;108:308-28; quiz 329.

25. Boeckxstaens G., et al. Gut 2014;63:1185-93.

26. Patel A., et al. Neurogastroenterol Motil. 2016;28:513-21.

27. Patel A., et al. Neurogastroenterol Motil. 2016;28:1382-90.

28. Martinucci I., et al. Neurogastroenterol Motil. 2014;26:546-55.

29. Ates F., et al. Gastroenterology 2015;148:334-43.

30. Kessing B.F., et al. Am J Gastroenterol. 2011;106:2093-7.

31. Patel A., et al. Aliment Pharmacol Ther. 2016;44:890-8.

32. Frazzoni M., et al. Neurogastroenterol Motil. 2016.

33. Frazzoni M., et al. Neurogastroenterol Motil. 2013;25:399-406, e295.

34. Vela M.F., et al. Am J Gastroenterol. 2011;106:844-50.
 

 

Introduction

Chronic esophageal symptoms attributed to gastroesophageal reflux disease (GERD) are common presenting symptoms in gastroenterology, leading to high healthcare costs and adverse quality of life globally.^1,2 The clinical diagnosis of GERD hinges on the presence of “troublesome” compatible typical symptoms (heartburn, acid regurgitation) or evidence of mucosal injury on endoscopy (esophagitis, Barrett’s esophagus, peptic stricture).³ With the growing availability of proton pump inhibitors (PPIs), patients and clinicians often utilize an empiric therapeutic trial of PPI as an initial test, with symptom improvement in the absence of alarm symptoms indicating a high likelihood of GERD.⁴ A meta-analysis of studies that used objective measures of GERD (in this case, 24-hour pH monitoring) showed that the “PPI test” has a sensitivity of 78%, but a specificity of only 54%, as a diagnostic approach to GERD symptoms.⁵ Apart from noncardiac chest pain, the diagnostic yield is even lower for atypical and extra-esophageal symptoms such as cough or laryngeal symptoms.⁶

Therefore, when symptoms persist despite seemingly adequate PPI therapy, esophageal investigation may start with endoscopy but continues with ambulatory reflux and motility testing.⁷ At endoscopy, exclusion of eosinophilic esophagitis with esophageal biopsies represents an important component of initial evaluation when symptoms are refractory to PPIs.⁸ Further, the more atypical the presentation, the greater the need for esophageal testing prior to long-term PPI therapy. Esophageal function testing is also indicated when confirmation of GERD is needed prior to surgical or endoscopic reflux procedures.
 

The “nuts and bolts” of reflux testing

Ambulatory reflux testing assesses esophageal reflux burden and symptom-reflux association (SRA). Individual reflux events are identified as either a drop in esophageal pH to less than 4 (acid reflux events), or a sharp decrease in esophageal impedance measurements in a retrograde fashion (impedance-detected reflux events), with subsequent recovery to the baseline in each instance. Ambulatory reflux testing affords insight into three areas: 1) measurement of esophageal acid exposure time (AET); the cumulative time duration when distal esophageal pH is less than 4 at the recording site, reported as a percentage of the recording period; 2) measurement of the number of reflux events both acidic (from pH monitoring) and weakly acidic/alkaline (from impedance monitoring); and 3) quantitative evaluation of the association between reported symptom episodes and reflux events.

The three available modalities of ambulatory reflux monitoring consist of catheter-based pH, wireless pH, and combined catheter-based pH-impedance monitoring. Catheter-based pH monitoring, introduced in the 1970s, requires transnasal catheter placement and typically records for 24 hours before catheter removal. The catheter is positioned with the distal pH sensor 5 cm proximal to the upper margin of the manometrically identified lower esophageal sphincter (LES). New guidelines suggest AET less than 4% is reliably normal, while AET greater than 6% is pathologic; values in between are considered borderline and require alternate evidence for GERD, such as endoscopic findings.⁷ Wireless pH probes are placed 6 cm proximal to the squamocolumnar junction at endoscopy and communicate with a pager-sized receiver worn by the patient.⁹ Patient comfort is not compromised, with less restriction of typical patient activities compared to catheter-based testing, facilitating longer recording periods of 48-96 hours, which can overcome day-to-day variations in esophageal reflux burden.⁷ With catheter-based pH-impedance monitoring, multiple pairs of impedance sensors measure the resistance to flow of a tiny electrical current between sensors. Since resistance to flow (that is, impedance) is low in the presence of a bolus or refluxate in the esophageal lumen, the impedance tracing drops during reflux events in a retrograde fashion across the esophageal impedance sensor pairs, regardless of the acidity of the reflux (Figure 1).¹⁰ Combined pH-impedance testing thus detects refluxate in the esophagus regardless of pH, improving the sensitivity of detection of reflux events over pH testing alone, thereby promoting greater yield of SRA. However, there remains wide inter-observer variation on the designation of impedance reflux events.¹¹

The two most commonly utilized SRA metrics are the symptom index (SI) and symptom-association probability (SAP). Individual symptom episodes are designated as related to preceding reflux events if they occur within 2 minutes of the reflux events. The SI represents the simple ratio of the number of reflux-related symptoms to the total number of symptom episodes reported during the ambulatory reflux study, with values above 50% designated as positive.¹² For calculation of the SAP, the ambulatory reflux study is divided into 2-minute intervals. For each interval, the presence or absence of a reflux event and a symptom episode is assessed; the final counts are tabulated on a 2 x 2 table, and a Fisher exact test is applied to generate a “P” value. The SAP is positive if P is less than 0.05, corresponding to an SAP of greater than 95%, or a less than 5% chance that the observed association between symptoms and reflux events occurred by chance.¹³ The SAP can also be calculated post-hoc with data typically extracted during a pH study, using statistical modeling; termed the Ghillebert Probability Estimate,¹⁴ this corresponds well with the former method of SAP calculation.¹⁵

The SI and SAP can be calculated individually for acid-detected reflux events and for impedance-detected reflux events. Since reflux events are better detected with impedance, combined pH-impedance testing increases the yield of detecting positive SRA, especially when performed off PPI therapy.^16,17 Because these indices are heavily reliant on patient reporting of symptom episodes, SRA can be overinterpreted;¹⁸ positive associations are more clinically useful than negative results in the evaluation of symptoms attributed to GERD.¹⁹ Despite these concerns, the two most consistent predictors of symptomatic outcome with antireflux therapy on pH-impedance testing are abnormal AET and positive SAP with impedance-detected reflux events.¹⁷

Copyright Elsevier/AGA

Along with reflux testing, an esophageal high-resolution manometry (HRM) study is typically performed to establish the location of the LES for placement of reflux catheters. Beyond this primary indication, HRM serves the important role of excluding significant esophageal motor disorders in these patients, particularly achalasia spectrum disorders.²⁰ Despite a diametrically opposite pathophysiology compared to GERD, achalasia can present with retrosternal discomfort (often interpreted as heartburn) and esophageal regurgitation (potentially interpreted as acid regurgitation).²¹ Therefore, achalasia spectrum disorders can be mistaken for GERD and managed with acid suppression, thereby contributing to the pool of symptomatic patients refractory to PPI therapy. HRM has high accuracy and specificity for the diagnosis of achalasia and other major esophageal motor disorders.²² Other foregut disorders diagnosed using HRM (typically combined HRM and impedance, or HRiM) include rumination and supragastric belching. The exclusion of a major esophageal motor disorder is also a requirement for the diagnosis of a functional esophageal disorder, where esophageal reflux testing is normal.²³

 

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

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

Conclusions

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.

 

References

1. Shaheen N.J., et al. Am J Gastroenterol. 2006;101:2128-38.

2. Patel A., Gyawali C.P.. Switzerland: Springer International, 2016.

3. Vakil N., et al. Am J Gastroenterol. 2006;101:1900-20; quiz 1943.

4. Fass R., et al. Arch Intern Med. 1999;159:2161-8.

5. Numans M.E., et al. Ann Intern Med. 2004;140:518-27.

6. Shaheen N.J., et al. Aliment Pharmacol Ther. 2011;33:225-34.

7. Roman S., et al. Neurogastroenterol Motil Mar 31. doi: 10.1111/nmo.13067. [Epub ahead of print] 2017.

8. Dellon E.S., et al. Am J Gastroenterol. 2013;108:679-92; quiz 693.

9. Pandolfino JE, Vela MF. Gastrointest Endosc. 2009;69:917-30, 930 e1.

10. Shay S., et al. Am J Gastroenterol. 2004;99:1037-43.

11. Zerbib F., et al. Clin Gastroenterol Hepatol. 2013;11:366-72.

12. Wiener G.J., et al. Am J Gastroenterol 1988;83:358-61.

13. Weusten B.L., et al. Gastroenterology. 1994;107:1741-5.

14. Ghillebert G., et al. Gut 1990;31:738-44.

15. Kushnir V.M., et al. Aliment Pharmacol Ther. 2012;35(9):1080-7.

16. Bredenoord A.J., et al. Am J Gastroenterol. 2006;101:453-9.

17. Patel A., et al. Clin Gastroenterol Hepatol. 2015;13:884-91.

18. Slaughter J.C., et al. Clin Gastroenterol Hepatol. 2011;9:868-74.

19. Kavitt R.T., et al. Am J Gastroenterol. 2012;107:1826-32.

20. Kahrilas P.J., et al. Gastroenterology 2008;135:1383-91, 1391 e1-5.

21. Kessing B.F., et al. Clin Gastroenterol Hepatol. 2011;9:1020-4.

22. Kahrilas P.J., et al. Neurogastroenterol Motil. 2015;27:160-74.

23. Aziz A, et al. Esophageal disorders. Gastroenterology 2016;150:1368-79.

24. Katz P.O., et al. Am J Gastroenterol. 2013;108:308-28; quiz 329.

25. Boeckxstaens G., et al. Gut 2014;63:1185-93.

26. Patel A., et al. Neurogastroenterol Motil. 2016;28:513-21.

27. Patel A., et al. Neurogastroenterol Motil. 2016;28:1382-90.

28. Martinucci I., et al. Neurogastroenterol Motil. 2014;26:546-55.

29. Ates F., et al. Gastroenterology 2015;148:334-43.

30. Kessing B.F., et al. Am J Gastroenterol. 2011;106:2093-7.

31. Patel A., et al. Aliment Pharmacol Ther. 2016;44:890-8.

32. Frazzoni M., et al. Neurogastroenterol Motil. 2016.

33. Frazzoni M., et al. Neurogastroenterol Motil. 2013;25:399-406, e295.

34. Vela M.F., et al. Am J Gastroenterol. 2011;106:844-50.
 

 

Introduction

Chronic esophageal symptoms attributed to gastroesophageal reflux disease (GERD) are common presenting symptoms in gastroenterology, leading to high healthcare costs and adverse quality of life globally.^1,2 The clinical diagnosis of GERD hinges on the presence of “troublesome” compatible typical symptoms (heartburn, acid regurgitation) or evidence of mucosal injury on endoscopy (esophagitis, Barrett’s esophagus, peptic stricture).³ With the growing availability of proton pump inhibitors (PPIs), patients and clinicians often utilize an empiric therapeutic trial of PPI as an initial test, with symptom improvement in the absence of alarm symptoms indicating a high likelihood of GERD.⁴ A meta-analysis of studies that used objective measures of GERD (in this case, 24-hour pH monitoring) showed that the “PPI test” has a sensitivity of 78%, but a specificity of only 54%, as a diagnostic approach to GERD symptoms.⁵ Apart from noncardiac chest pain, the diagnostic yield is even lower for atypical and extra-esophageal symptoms such as cough or laryngeal symptoms.⁶

Therefore, when symptoms persist despite seemingly adequate PPI therapy, esophageal investigation may start with endoscopy but continues with ambulatory reflux and motility testing.⁷ At endoscopy, exclusion of eosinophilic esophagitis with esophageal biopsies represents an important component of initial evaluation when symptoms are refractory to PPIs.⁸ Further, the more atypical the presentation, the greater the need for esophageal testing prior to long-term PPI therapy. Esophageal function testing is also indicated when confirmation of GERD is needed prior to surgical or endoscopic reflux procedures.
 

The “nuts and bolts” of reflux testing

Ambulatory reflux testing assesses esophageal reflux burden and symptom-reflux association (SRA). Individual reflux events are identified as either a drop in esophageal pH to less than 4 (acid reflux events), or a sharp decrease in esophageal impedance measurements in a retrograde fashion (impedance-detected reflux events), with subsequent recovery to the baseline in each instance. Ambulatory reflux testing affords insight into three areas: 1) measurement of esophageal acid exposure time (AET); the cumulative time duration when distal esophageal pH is less than 4 at the recording site, reported as a percentage of the recording period; 2) measurement of the number of reflux events both acidic (from pH monitoring) and weakly acidic/alkaline (from impedance monitoring); and 3) quantitative evaluation of the association between reported symptom episodes and reflux events.

The three available modalities of ambulatory reflux monitoring consist of catheter-based pH, wireless pH, and combined catheter-based pH-impedance monitoring. Catheter-based pH monitoring, introduced in the 1970s, requires transnasal catheter placement and typically records for 24 hours before catheter removal. The catheter is positioned with the distal pH sensor 5 cm proximal to the upper margin of the manometrically identified lower esophageal sphincter (LES). New guidelines suggest AET less than 4% is reliably normal, while AET greater than 6% is pathologic; values in between are considered borderline and require alternate evidence for GERD, such as endoscopic findings.⁷ Wireless pH probes are placed 6 cm proximal to the squamocolumnar junction at endoscopy and communicate with a pager-sized receiver worn by the patient.⁹ Patient comfort is not compromised, with less restriction of typical patient activities compared to catheter-based testing, facilitating longer recording periods of 48-96 hours, which can overcome day-to-day variations in esophageal reflux burden.⁷ With catheter-based pH-impedance monitoring, multiple pairs of impedance sensors measure the resistance to flow of a tiny electrical current between sensors. Since resistance to flow (that is, impedance) is low in the presence of a bolus or refluxate in the esophageal lumen, the impedance tracing drops during reflux events in a retrograde fashion across the esophageal impedance sensor pairs, regardless of the acidity of the reflux (Figure 1).¹⁰ Combined pH-impedance testing thus detects refluxate in the esophagus regardless of pH, improving the sensitivity of detection of reflux events over pH testing alone, thereby promoting greater yield of SRA. However, there remains wide inter-observer variation on the designation of impedance reflux events.¹¹

The two most commonly utilized SRA metrics are the symptom index (SI) and symptom-association probability (SAP). Individual symptom episodes are designated as related to preceding reflux events if they occur within 2 minutes of the reflux events. The SI represents the simple ratio of the number of reflux-related symptoms to the total number of symptom episodes reported during the ambulatory reflux study, with values above 50% designated as positive.¹² For calculation of the SAP, the ambulatory reflux study is divided into 2-minute intervals. For each interval, the presence or absence of a reflux event and a symptom episode is assessed; the final counts are tabulated on a 2 x 2 table, and a Fisher exact test is applied to generate a “P” value. The SAP is positive if P is less than 0.05, corresponding to an SAP of greater than 95%, or a less than 5% chance that the observed association between symptoms and reflux events occurred by chance.¹³ The SAP can also be calculated post-hoc with data typically extracted during a pH study, using statistical modeling; termed the Ghillebert Probability Estimate,¹⁴ this corresponds well with the former method of SAP calculation.¹⁵

The SI and SAP can be calculated individually for acid-detected reflux events and for impedance-detected reflux events. Since reflux events are better detected with impedance, combined pH-impedance testing increases the yield of detecting positive SRA, especially when performed off PPI therapy.^16,17 Because these indices are heavily reliant on patient reporting of symptom episodes, SRA can be overinterpreted;¹⁸ positive associations are more clinically useful than negative results in the evaluation of symptoms attributed to GERD.¹⁹ Despite these concerns, the two most consistent predictors of symptomatic outcome with antireflux therapy on pH-impedance testing are abnormal AET and positive SAP with impedance-detected reflux events.¹⁷

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Along with reflux testing, an esophageal high-resolution manometry (HRM) study is typically performed to establish the location of the LES for placement of reflux catheters. Beyond this primary indication, HRM serves the important role of excluding significant esophageal motor disorders in these patients, particularly achalasia spectrum disorders.²⁰ Despite a diametrically opposite pathophysiology compared to GERD, achalasia can present with retrosternal discomfort (often interpreted as heartburn) and esophageal regurgitation (potentially interpreted as acid regurgitation).²¹ Therefore, achalasia spectrum disorders can be mistaken for GERD and managed with acid suppression, thereby contributing to the pool of symptomatic patients refractory to PPI therapy. HRM has high accuracy and specificity for the diagnosis of achalasia and other major esophageal motor disorders.²² Other foregut disorders diagnosed using HRM (typically combined HRM and impedance, or HRiM) include rumination and supragastric belching. The exclusion of a major esophageal motor disorder is also a requirement for the diagnosis of a functional esophageal disorder, where esophageal reflux testing is normal.²³

 

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

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

Conclusions

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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