Secondary Logo

Journal Logo

ESOPHAGUS: Edited by Stuart J. Spechler

Management of regurgitation in patients with gastroesophageal reflux disease

Bell, Reginald C.W.

Author Information
Current Opinion in Gastroenterology: July 2020 - Volume 36 - Issue 4 - p 336-343
doi: 10.1097/MOG.0000000000000649

Abstract

INTRODUCTION

Heartburn and regurgitation are the symptoms most commonly associated with gastroesophageal reflux disease (GERD). Heartburn, that is, substernal burning or chest pain, is generally considered the sine qua non symptom of GERD. Regurgitation, a bitter taste in the mouth or an unpleasant sense of fluid moving up from the stomach, has played second fiddle and is often overlooked as a meaningful, often troublesome symptom. Studies of medication use in GERD have all used alleviation of heartburn as a primary endpoint; occasionally regurgitation has been thrown in as a secondary endpoint [1]. The most common patient-reported outcome measure for surgical treatment of GERD, the GERD-health-related quality of life (HRQL), has no questions regarding regurgitation [2]. Yet as disease management moves towards precision care, heartburn, and regurgitation are emerging as distinct subtypes of GERD that, though often coexisting, may have different physiologic mechanisms and responses to therapy. 

Box 1
Box 1:
no caption available

DEFINITION AND ASSESSMENT OF REGURGITATION

Regurgitation can be defined as the sensation of stomach contents moving up the esophagus and/or a bitter taste or fluid in the mouth. Research on outcomes of medical therapy have typically recognized two symptom categories, movement, and taste, even though not all experts are in agreement about whether movement in the chest without accompanying pharyngeal reflux and acid taste constitutes regurgitation [3]. The Reflux Disease Questionnaire (RDQ) is a validated scoring system that asks patients to rate the severity and frequency of their GERD symptoms by two questions each regarding heartburn, regurgitation, and dyspepsia (Appendix A, http://links.lww.com/COG/A31). The two questions related to reflux are whether the patient experiences [1] an acid taste in the mouth (regurgitation – taste), or [2] unpleasant movement of material upwards from the stomach (regurgitation – movement) [4]. A reasonable correlation between the frequency with which these two symptoms are reported has been found, though in studies of patients presenting with severe substernal burning, regurgitation – taste was reported in a slightly higher percentage of (85%) than was regurgitation – movement (75%) [5].

Clinical outcome studies of surgical interventions for GERD have often used the GastroEsophageal Disease Health-Related Quality of Life (GERD-HRQL), which does not measure regurgitation symptoms, or used a vaguely defined ‘acid regurgitation’ symptom [6]. More recently, surgical outcome studies have variously measured regurgitation with the RDQ, as well as the Foregut Symptom Questionnaire (FSQ), the Gastroesophageal Reflux Symptom Score, and a Regurgitation score adapting the GERD-HRQL grading but substituting ‘regurgitation’ for ‘heartburn’ (Appendix B, http://links.lww.com/COG/A32) [7–10].

DIFFERENTIAL DIAGNOSIS

Regurgitation can also be reported in patients with achalasia or esophago-gastric junction outflow obstruction. However, the content typically will not have gastric acid or bile, and will frequently consist of undigested food, or fluid and saliva.

Rumination occurs while or immediately after eating and is associated with an increase in intragastric pressure which overcomes the reflux barrier. Although it can coexist with GERD, rumination is often not associated with heartburn and the reflux sensation may not be unpleasant, helping to differentiate it from GERD-associated regurgitation [11].

In equivocal cases, impedance-manometric studies will often clarify the diagnosis [12].

FREQUENCY AND IMPACT OF REGURGITATION ON QUALITY OF LIFE

Regurgitation and heartburn frequently coexist. In patient with frequent, intense heartburn, regurgitation-taste was present in 86%, regurgitation-movement in 77%, and either in 93%. Increased frequency of regurgitation correlated with a decrease in global quality of life, and daily regurgitation nearly equaled the decrease of frequent, intense heartburn [13]. Experiencing regurgitation between 3 and 4 days/week has been suggested as a useful threshold for having a clinically meaningful effect on quality of life [14].

Heartburn generally has a greater impact on quality of life than regurgitation when both are present [15]. When heartburn was been eliminated by acid-suppressive medication (ASM), frequent regurgitation (≥4 days/week) persisted in 28% of patients with nonerosive reflux disease (NERD) and 23% of patients with erosive esophagitis. Persistent, frequent regurgitation has a detrimental impact on quality of life even when heartburn responds excellently to ASM.

Regurgitation, regardless of degree of heartburn, affects quality of life as assessed not only by food or drink disruption but by emotional distress, sleep disruption, physical/social function, and vitality. Over-the-counter medication use and missed work hours/week are increased in patients with at least 3 days/week of regurgitation. In patients with no or infrequent heartburn, ongoing sleep disruption has been reported by 50–60% with persistent, frequent regurgitation, compared with 38–51% and 14–19% of those with less frequent or no regurgitation respectively. Higher frequencies of regurgitation were associated with an increased negative impact on sleep, regardless of whether the patients had absent or infrequent, mild heartburn [13,14].

DIFFERENTIAL RESPONSE OF REGURGITATION AND HEARTBURN TO MEDICAL THERAPY

Even though response of regurgitation has not been a primary endpoint of studies of medical therapy, when it has been assessed, regurgitation does not respond as well as heartburn to acid suppression.

A retrospective analysis of response of high severity heartburn and regurgitation among nearly 3000 patients found a lower response rate (RR) for complete resolution of regurgitation symptoms compared with heartburn symptoms in patients treated with 4 weeks of either esomeprazole or AZD0865, a potassium-competitive acid blocker, Fig. 1[5]. At entry, 93% of patients reported regurgitation, and roughly 55% reported it more than 3 days/week.

FIGURE 1
FIGURE 1:
Proportion of patients with complete response to 4 weeks of acid suppressive medication. Complete resolution indicates no report of the item for all 7 days.

Regurgitation-taste improved with medical therapy in a greater percentage of patients than did regurgitation-movement (44% taste vs. 33% movement in erosive esophagitis, and 34% vs. 26% in NERD), regardless of the severity of symptoms at presentation. And although healing of erosive esophagitis was observed in ∼80% of patients by 4 weeks, complete resolution of substernal burning was reported in only ∼50% of patients (there is a common misperception that severe heartburn completely resolves with potent ASM in almost all patients).

A second analysis found regurgitation outcomes reported in 31 of 135 clinical trials of proton pump inhibitor (PPI), but in none was regurgitation a primary endpoint [16]. Trials using ‘acid regurgitation’ synonymously with ‘regurgitation’ were excluded. Eight placebo-controlled trials and seven PPI vs. H2-blocker or prokinetic met final criteria for analysis. These studies found the therapeutic gain of PPIs over placebo to average 17% (range from 0 to 35%) and over H2-blocker/prokinetic to average 20% (range from 5 to 38%,). This was significantly less than heartburn, in which the therapeutic gain above placebo was 42% (range 27–59) and was 30% (16–40) above other medications, Fig. 2.

FIGURE 2
FIGURE 2:
Comparison of therapeutic gain with respect to heartburn and regurgitation relief relative to placebo.

That regurgitation persists and affects quality of life in 13–25% of patients whose heartburn responds to ASM is important in at least three respects: first, regurgitation may be a fairly common characteristic in the group of patients, up to 40% in some studies, who express dissatisfaction with their medical therapy; second, regurgitation does not respond as well to ASM as heartburn; and third, failure of regurgitation to respond to medical therapy should not be taken to imply that regurgitation is not due to GERD, but rather that it may have a different mechanism than acid-sensitivity.

Many agents including prokinetics have been studied as an ‘add-on’ to once-daily PPI therapy in patients with refractory regurgitation and have, for the most part, not been able to outperform placebo [17].

MECHANISMS OF REGURGITATIVE SYMPTOMS

Volume of reflux

Howden performed gastric juice analysis in humans before and after treatment with omeprazole in both the fasting (basal) state and after pentagastrin stimulation. Both basal and stimulated acid output decreased by over 98% after 7 days of either 30 or 60 mg of omeprazole. Although volume of gastric juice secretion decreased, 7 days of 30 mg omeprazole resulted in a 55% (basal) and 79% (stimulated) reduction, and 60 mg omeprazole produced only a minimal improvement beyond 30 mg (62 and 84%, respectively), Fig. 3.

FIGURE 3
FIGURE 3:
Volume of gastric juice secretion and acid output after 30 or 60 mg of Omeprazole. Fasting is the basal state, the stimulated state is post pentagastrin stimulation.

From this study we can infer that PPIs reduce gastric juice secretion to a lesser extent than they do gastric acid output. This may help explain why PPIs do reduce regurgitative symptoms (less gastric juice) but not as much as they reduce heartburn (almost no gastric acid production). Secondly, 60 mg omeprazole only minimally decreased the amount of gastric juice secreted compared with 30 mg, which may explain the results of studies comparing antireflux procedures to increased PPI dosing in refractory regurgitation, which are discussed below.

Proximal extent of reflux

Impedance/pH testing allows evaluation both of proximal extent of reflux and can distinguish nonacidic, weakly acidic, and acidic reflux events. Studies of patients off ASMs have found that immediate prior acidic reflux events (sensitization), proximal extent of reflux, lower nadir pH, longer volume, and acid clearance time were associated with reflux perception and were more likely to be associated with symptoms; and the proximal extent of episodes preceding regurgitation was greater than those preceding heartburn (mean 11 vs. 15 cm), as was the likelihood of a gaseous component in the reflux episodes preceding the regurgitation [18].

Zerbib utilized impedance/pH testing with symptom correlation to evaluate persistent GERD symptoms in 20 patients refractory to twice-daily PPIs. High-proximal extent of reflux events was the only factor associated with reflux perception, and the study did suggest that the perception of heartburn is more sensitive than regurgitation to the chemical composition of the refluxate [19].

Significantly, studies using impedance/pH testing found a lower frequency of proximal reflux events after clinically successful surgical treatment of GERD by transoral fundoplication, even when pH was not normalized [20].

Weakly acidic reflux

In a study of 145 patients with refractory symptoms despite PPI twice daily, patients were studied ‘on’ PPI. Whereas 13 and 8%, respectively, of heartburn and regurgitation events were associated with acid reflux (pH < 4), 27 and 58% of the heartburn and regurgitation events, respectively, were associated with weakly acidic reflux (pH 4–7) [21,22].

Upper esophageal sphincter dysfunction

Gerhardt found that patients with esophagopharyngeal regurgitation have lower esophageal sphincter hypotension, diminished peristaltic amplitude, upper esophageal sphincter hypotension, and diminished upper esophageal sphincter response to intraesophageal fluid [23].

RESPONSE TO SURGICAL THERAPY

To the author's knowledge, no trial of laparoscopic fundoplication has used regurgitation as a primary endpoint, though some have used it as a secondary endpoint or used ‘acid regurgitation’ and/or heartburn as a definition of treatment failure. However, recent trials using newer antireflux procedures have used regurgitation as a primary endpoint in comparing these procedures to medical therapy for regurgitation-refractory GERD. Two have used Transoral Incisionless Fundoplication (TIF) with the EsophyX device (EndoGastric Solutions, Redmond, Washington, USA) and one compared Magnetic Sphincter Augmentation (MSA) with the LINX device (Ethicon Endo-Surgery, Somerville, New Jersey, USA) to PPI therapy. Unlike the medical trials mentioned above, abnormal ambulatory pH testing (off medication) was an entry requirement for all these studies. Though not the purpose of this review, these newer procedures have demonstrated efficacy and durability with an excellent safety profile and fewer side effects than traditional laparoscopic fundoplication.

Randomized EsophyX vs. Sham, Placebo-Controlled Transoral Fundoplication (RESPECT) A sham-controlled randomized controlled trial compared TIF using the EsophyX2 device to increased PPI dosing in 129 patients with troublesome regurgitation, defined as mild symptoms for 2 or more days/week or moderate-to-severe symptoms more than 1 day/week despite at least 40 mg/day of PPIs [24]. Patients with GERD and hiatal hernias of 2 cm or less were randomly assigned to receive TIF and then received 6 months of placebo (n = 87), or to sham procedure (EsophagoGastroDuodenoscopy (EGD) with manipulation of a Maloney dilator under general anesthesia) followed by 6 months of once-daily or twice-daily omeprazole (controls, n = 42). Patients were blinded to therapy during follow-up period and reassessed at 2, 12, and 26 weeks. At 6 months, patients underwent 48-h esophageal pH monitoring and EGD. At 3 months follow-up, 12/42 patients in the sham group underwent crossover to TIF due to early failure, and 10/87 TIF patients returned to PPI treatment for early failure. By intention-to-treat analysis, at 6 months TIF eliminated troublesome regurgitation in a larger proportion of patients (67%) than PPIs (45%) (P = 0.23).

Control of esophageal pH improved after TIF (mean 9.3% before and 6.3% after; P < 0.01), but not after sham surgery (mean 8.6% before and 8.9% after). As in other studies of antireflux procedures, no correlation was found between pH normalization and symptom relief.

Transoral incisionless fundoplication EsophyX vs. Medical Proton Pump inhibitor Open Label Trial

A multicenter study randomized 63 patients with daily troublesome regurgitation or extraesophageal symptoms on daily PPIs to TIF using the EsophyX2 device (40 patients) or to maximized standard dosing (MSD) of PPI (following manufacturers guidelines for dosing, 23 patients) [25]. At enrollment, 30 of the 40 TIF patients reported troublesome regurgitation, and 29 (97%) reported elimination 6 months after TIF, compared with 9/18 (50%) in the MSD PPI group. Esophageal pH normalized in 54% of the TIF group. No correlation was found between pH normalization and symptom relief. Long-term follow-up of the TIF group found prolonged relief of regurgitation in 90% at 3 years and 86% at 5 years [26▪▪].

Randomized controlled trial of LINX vs. double-dose proton pump inhibitor therapy for reflux disease (CALIBER)

MSA was compared with double-dose PPIs in 152 patients with moderate-to-severe regurgitation on single-dose PPI therapy [27▪▪]. Utilizing the FSQ, regurgitation was considered moderate if it was predictable with position change, straining, or lying down, and severe if constant or there was presence of aspiration symptoms [8]. Fifty patients underwent MSA and 102 patients were treated with double-dose PPI therapy. After 6 months, reassessment of symptoms and impedance/pH testing (on PPI in the PPI group, off PPI in the MSA group) were performed. Per protocol, 89% (42/47) of treated patients with MSA reported relief of moderate-to-severe regurgitation compared with 10% (10/101) of the twice-daily (BID) PPI group, Fig. 4. Eighty-one percentage of patients with MSA had at least 50% improvement in GERD-HRQL scores compared with 8% of patients treated with BID PPI. Ninety-one percentage of MSA patients remained off of PPI therapy; no patient in the BID PPI group stopped medication. A normal number of reflux episodes and normal acid exposure was observed in 91 and 89% of MSA patients, respectively, compared with 58 and 75% of BID PPI patients at 6 months.

FIGURE 4
FIGURE 4:
Percentage of patients treated with magnetic sphincter augmentation or twice daily proton pump inhibitor therapy at the 6-month endpoint with no, mild, or moderate-to-severe regurgitation. MSA, magnetic sphincter augmentation; PPI, proton pump inhibitor.

At 6 months, patients in the BID PPI group who had ongoing moderate-severe regurgitation and an abnormal number of reflux episodes (>57/24 h) on impedance/pH testing on PPI therapy were eligible to crossover to MSA [28▪▪]. At 12 months all patients underwent quality of life surveys and 48 h capsule pH testing. Relief of moderate-severe regurgitation was comparable between the initial and crossover MSA groups [28▪▪]. Patients who reported no response of regurgitation to PPIs preoperatively had the same positive response to MSA as patients who had a partial response at entry, and quite interestingly the same held true for heartburn in this group, underscoring the unreliability of response to PPIs as a predictor of success of antireflux procedures in patients with typical symptoms and abnormal pH testing, Fig. 5.

FIGURE 5
FIGURE 5:
(a) Regurgitation and (b) heartburn scores for magnetic sphincter augmentation patients by response to proton pump inhibitors at baseline. Responder is defined by having at least a half standard deviation change between on and off gastroesophageal reflux disease medication scores at baseline.

Regurgitation is the symptom that responds best to antireflux procedures whereas the RRs for heartburn somewhat lower, suggesting again differing though overlapping causes of these symptoms [7,29,30].

DISCUSSION

Disease management is increasingly focused on the concept of precision care, and treating GERD in this fashion involves phenotyping by physiology and symptomatology. Regurgitation has largely been overlooked as a significant and distinct symptom of GERD. It can be characterized as a bitter taste in the mouth or a sense of fluid moving up from the stomach, and is reported in approximately 80% of GERD patients with varying severity. When heartburn and regurgitative symptoms coexist, as they often do, heartburn appears to affect quality of life to a greater degree.

Regurgitation still persists in upwards of 15% of patients even when heartburn is alleviated by ASM. It can result in a significant decrease in quality of life, especially when occurring more than 3 times/week. The symptom is probably mediated more by fluid volume than by the acidity of the refluxate; weakly acidic reflux and proximal extent of reflux may play a role.

PPIs significantly decrease gastric acid secretion and to some extent volume of gastric juice. Significantly, doubling the PPI dose does not incrementally decrease gastric juice volume though it may decrease gastric acid secretion further. Given the volume-related mechanism, it is not surprising that the therapeutic gain of PPIs over placebo is approximately 17% for regurgitation compared with 42% for heartburn, an acid-related symptom.

Antireflux procedures decrease and in some cases eliminate the reflux of gastric contents into the esophagus. Regurgitation is the symptom that responds best to antireflux surgery. Studies on refractory regurgitation using some of the newer antireflux procedures (MSA and transoral fundoplication) demonstrated success in over 85% of patients whereas increased PPI dosing helped in approximately 15%.

CONCLUSION

Current evidence indicates that regurgitation responds poorly to acid-suppressive therapy, and that antireflux procedures safely and far more effectively alleviate regurgitative symptoms.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

R.C.W.B. is a consultant for Ethicon Endo-Surgery.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

REFERENCES

1. Kahrilas PJ. Regurgitation in patients with gastroesophageal reflux disease. Gastroenterol Hepatol 2013; 9:37–39.
2. Velanovich V, Vallance SR, Gusz JR, et al. Quality of life scale for gastroesophageal reflux disease. J Am Coll Surg 1996; 183:217–224.
3. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101:1900–1920. quiz 43.
4. Shaw MJ, Talley NJ, Beebe TJ, et al. Initial validation of a diagnostic questionnaire for gastroesophageal reflux disease. Am J Gastroenterol 2001; 96:52–57.
5. Kahrilas PJ, Jonsson A, Denison H, et al. Regurgitation is less responsive to acid suppression than heartburn in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2012; 10:612–619.
6. Lundell L, Abrahamsson H, Ruth M, et al. Long-term results of a prospective randomized comparison of total fundic wrap (Nissen-Rossetti) or semifundoplication (Toupet) for gastro-oesophageal reflux. Br J Surg 1996; 83:830–835.
7. Ganz RA, Edmundowicz SA, Taiganides PA, et al. Long-term outcomes of patients receiving a magnetic sphincter augmentation device for gastroesophageal reflux. Clin Gastroenterol Hepatol 2016; 14:671–677.
8. Costantini M, Crookes PF, Bremner RM, et al. Value of physiologic assessment of foregut symptoms in a surgical practice. Surgery 1993; 114:780–786. discussion 6–7.
9. Bell RC, Barnes WE, Carter BJ, et al. Transoral incisionless fundoplication: 2-year results from the prospective multicenter U.S. study. Am Surg 2014; 80:1093–1105.
10. Allen CJ, Parameswaran K, Belda J, Anvari M. Reproducibility, validity, and responsiveness of a disease-specific symptom questionnaire for gastroesophageal reflux disease. Dis Esophagus 2000; 13:265–270.
11. Kessing BF, Smout AJ, Bredenoord AJ. Current diagnosis and management of the rumination syndrome. J Clin Gastroenterol 2014; 48:478–483.
12. Rommel N, Tack J, Arts J, et al. Rumination or belching-regurgitation? Differential diagnosis using oesophageal impedance-manometry. Neurogastroenterol Motil 2010; 22:e97–e104.
13. Kahrilas PJ, Jonsson A, Denison H, et al. Impact of regurgitation on health-related quality of life in gastro-oesophageal reflux disease before and after short-term potent acid suppression therapy. Gut 2014; 63:720–726.
14. Kahrilas PJ, Howden CW, Wernersson B, et al. Impact of persistent, frequent regurgitation on quality of life in heartburn responders treated with acid suppression: a multinational primary care study. Aliment Pharmacol Ther 2013; 37:1005–1010.
15. Lee SW, Lien HC, Lee TY, et al. Heartburn and regurgitation have different impacts on life quality of patients with gastroesophageal reflux disease. World J Gastroenterol 2014; 20:12277–12282.
16. Kahrilas PJ, Howden CW, Hughes N. Response of regurgitation to proton pump inhibitor therapy in clinical trials of gastroesophageal reflux disease. Am J Gastroenterol 2011; 106:1419–1425. quiz 26.
17. DeVault KR. Refractory regurgitation responds to magnetic sphincter augmentation but not to increased proton pump inhibitor dose. Gastrointest Endosc 2019; 89:23–24.
18. Bredenoord AJ, Weusten BLAM, Curvers WL, et al. Determinants of perception of heartburn and regurgitation. Gut 2006; 55:313–318.
19. Zerbib F, Duriez A, Roman S, et al. Determinants of gastro-oesophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors. Gut 2008; 57:156–160.
20. Rinsma NF, Smeets FG, Bruls DW, et al. Effect of transoral incisionless fundoplication on reflux mechanisms. Surg Endosc 2014; 28:941–949.
21. Sifrim D, Mittal R, Fass R, et al. Review article: acidity and volume of the refluxate in the genesis of gastro-oesophageal reflux disease symptoms. Aliment Pharmacol Ther 2007; 25:1003–1017.
22. Mainie I, Tutuian R, Hila A. Symptom type on PPI therapy does not predict reflux identified by MII-pH. Gastroenterology 2006; 130.
23. Gerhardt DC, Castell DO, Winship DH, Shuck TJ. Esophageal dysfunction in esophagopharyngeal regurgitation. Gastroenterology 1980; 78 (5 Pt 1):893–897.
24. Hunter JG, Kahrilas PJ, Bell RC, et al. Efficacy of transoral fundoplication vs omeprazole for treatment of regurgitation in a randomized controlled trial. Gastroenterology 2015; 148:324–333.e5.
25. Trad KS, Barnes WE, Simoni G, et al. Transoral incisionless fundoplication effective in eliminating GERD symptoms in partial responders to proton pump inhibitor therapy at 6 months: the TEMPO randomized clinical trial. Surg Innov 2015; 22:26–40.
26▪▪. Trad KS, Barnes WE, Prevou ER, et al. The TEMPO trial at 5 years: transoral fundoplication (TIF 2.0) is safe, durable, and cost-effective. Surg Innov 2018; 25:149–157.
27▪▪. Bell R, Lipham J, Louie B, et al. Laparoscopic magnetic sphincter augmentation versus double-dose proton pump inhibitors for management of moderate-to-severe regurgitation in GERD: a randomized controlled trial. Gastrointest Endosc 2018; 89:14–22.e1.
28▪▪. Bell R, Lipham J, Louie BE, et al. Magnetic sphincter augmentation superior to proton pump inhibitors for regurgitation in a 1-year randomized trial. Clin Gastroenterol Hepatol 2019; S1542-3565:30978–30974.
29. Bell RC, Mavrelis PG, Barnes WE, et al. A prospective multicenter registry of patients with chronic gastroesophageal reflux disease receiving transoral incisionless fundoplication. J Am Coll Surg 2012; 215:794–809.
30. Anvari M, Allen C, Marshall J, et al. A randomized controlled trial of laparoscopic Nissen fundoplication versus proton pump inhibitors for treatment of patients with chronic gastroesophageal reflux disease: one-year follow-up. Surg Innov 2006; 13:238–249.
Keywords:

magnetic sphincter augmentation; regurgitation; transoral incisionless fundoplication

Supplemental Digital Content

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.