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 . 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 . 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.
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 . 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  an acid taste in the mouth (regurgitation – taste), or  unpleasant movement of material upwards from the stomach (regurgitation – movement) . 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%) .
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 . 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].
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 .
In equivocal cases, impedance-manometric studies will often clarify the diagnosis .
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 . 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 .
Heartburn generally has a greater impact on quality of life than regurgitation when both are present . 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. At entry, 93% of patients reported regurgitation, and roughly 55% reported it more than 3 days/week.
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 . 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.
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 .
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.
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 .
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 .
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 .
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 .
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 . 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) . 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 . 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.
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.
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].
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%.
Current evidence indicates that regurgitation responds poorly to acid-suppressive therapy, and that antireflux procedures safely and far more effectively alleviate regurgitative symptoms.
Financial support and sponsorship
Conflicts of interest
R.C.W.B. is a consultant for Ethicon Endo-Surgery.
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