© Springer International Publishing AG 2018Eytan Bardan and Reza Shaker (eds.)Gastrointestinal Motility Disorders doi.org/10.1007/978-3-319-59352-4_9
Department of Medicine, Mayo Clinic Florida, Jacksonville, FL, USA
Kenneth R. DeVault
Question: Food and Liquid Are Coming Up in My Throat. What Is Causing This?
This sounds like regurgitation but asking the patient several other questions can better characterize the situation:
Is there associated heartburn? If the patient is on an acid blocker, you may have to ask if they used to have heartburn but do not anymore. Another way to ask this question is “do your symptoms worsen when you miss a dose of medication?” Some have argued that stopping PPI may exacerbate symptoms due to rebound acid production. While this may happen, the question and maneuver are still helpful, especially when the patient has no worsening after stopping the medication. The combination of heartburn and regurgitation is fairly specific for gastroesophageal reflux (GER) . Reflux-related regurgitation typically is not associated with nausea, retching, or abdominal pain, although reflux can overlap with any of those symptoms.
When this happens, does food come up? If food comes up during a meal, it is less likely reflux and could be due to an esophageal motility disorder or perhaps rumination. If it happens in the immediate postprandial period, it could still be from esophageal stasis but also may be reflux from the stomach. If it is 2 or more hours after a meal, then delayed stomach emptying is more likely.
Do you actually spit the material out or does it feel like it is coming up but does not and do you ever have it come back up into your mouth and then reswallow it? Regurgitation associated with GER usually does not come all the way into the mouth or is spit out. If that is happening, an esophageal disorder like achalasia should be considered. In fact, in patients with primary regurgitation and no heartburn, the GERD diagnosis can be erroneous in a number of patients who actually have achalasia . The concept of regurgitating into the mouth and then reswallowing is suggestive of rumination. Like regurgitation, rumination is not usually preceded by retching (which is seen with vomiting) . Water brash is often confused with regurgitation, but is a feeling of a large amount of bicarbonate-rich material appearing in the mouth, often as a reflex response to acid in the esophagus .
Question: I Have Reflux and Used to Have Heartburn, but It Doesn’t Happen When I am on My Acid Blocker. I Still Have Liquid Coming Up, Particularly at Night and It Makes Me Cough? What Is Causing This and What Can I Do?
Heartburn and regurgitation are more sensitive and specific symptoms for GER compared to all other symptoms . On the other hand, even combining these symptoms with response to PPI only results in a sensitivity of 78% and specificity of 54% . It has also been estimated that between 10 and 40% of patients with GERD do not respond completely to PPI therapy . There is substantial overlap between GERD and functional dyspepsia. Symptoms such as postprandial fullness, nausea, vomiting, and early satiety can be misinterpreted as or coexist with regurgitation. Patients with those symptoms tend to not respond as well to reflux therapy . Since drugs that address the underlying motility problem in GERD have, for the most part, not been successfully developed, most patients with GER are treated with acid blockers. These agents relieve heartburn and despite the fact that they really do not change the underlying physiology actually do improve regurgitation, but improve it less than they do for the symptom of heartburn. In a systematic review of the response of regurgitation to PPI therapy, there was an overall 17% improvement compared to placebo but heartburn showed an improvement of 37% compared to placebo . Refractory heartburn, regurgitation, or both can be seen in up to 32–45% of GERD patients treated with PPI . There is incomplete consensus on what is required before declaring a patient “refractory” but most commonly these patients are initially treated with once-daily PPI and then increased to twice daily before declaring failure . Regurgitation is considered by some to be the major contributor to unsatisfactory response in many patients . When impedance testing was compared to symptom production, episodes that led to the symptom of regurgitation were more likely to extend further up the esophagus (proximal) than those leading to “heartburn” . These interesting data make sense, since a small amount of acid could activate mucosal, acid-sensitive receptors, but one would think that regurgitation would require a sufficient volume to perhaps distend the esophagus.
When a patient presents with refractory regurgitation felt to be GERD-related, reflux surgery is often considered. It is critical that the diagnosis is very clear prior to that decision. The clinical history is key but not sufficient. Large hernias are well diagnosed on barium testing and can lead to surgery, but the demonstration of reflux on barium swallow is neither specific nor sensitive for pathologic GERD . Likewise, endoscopy can be suggestive and at times confirmatory. Esophagitis is specific with LA-B or greater. Redness, LA-A, or less is less specific. Barrett’s esophagus can also confirm pathologic reflux, but using this “diagnosis” is challenging since many patients are labeled as such have irregular squamocolumnar junctions and even normal anatomy due to the widespread practice of biopsy of this area. These patients may or may not have pathologic reflux.
While it would seem to make sense that refractory reflux-related regurgitation is caused by reflux of large amounts of neutralized gastric content into the esophagus, there are other possibilities. These include esophageal hypersensitivity (the experience of symptoms with normal or physiological volumes of reflux), poor esophageal clearance, or perhaps both. So, prior to considering anything beyond medical therapy, most patients will need their reflux confirmed with ambulatory reflux testing . How should this testing be performed? Tube or probe based? On or off therapy? With or without impedance? The question here is whether or not the patient has reflux, so an off-therapy test is most appropriate . For heartburn and regurgitation, the method of the test (tube or probe based) is not that important (assuming that the patient is not on acid-blocking medications) nor does impedance add a great deal. Dual-channel and impedance-based tests do have an advantage of faster sampling rates and the ability to estimate the height of reflux episodes, which may be helpful in some patients particularly those with proximal symptoms. As above noted, reflux episodes leading to the symptom of regurgitation tend to reach the proximal esophagus more often than those producing heartburn. The outcome of pH testing provides a guide to future therapy. Patients with abnormal acid exposure (>5%) and particularly those with severe acid exposure (>10%) have confirmed reflux and do not need additional testing. Another group will have normal esophageal acid exposure but a positive symptom association between their reflux events and symptoms. There are little data on the use of symptom association with the symptom of regurgitation, so care should be taken in interpreting those studies. Finally, some patients will have a normal study with a negative symptom association. They likely do not have reflux as a cause of their symptoms, although there is a small, but real false-negative rate with pH testing. There are some suggestions that refractory symptoms, including regurgitation, can be caused by a mixture of liquid and gas reflux . This may be due to distention of the esophagus rather than activation of chemoreceptors. These events can be seen with impedance testing and are missed with testing that only looks at esophageal pH.
The indication for on-therapy testing is much less clear. There are some patients who have abnormal acid exposure despite BID PPI therapy, but more often the overall exposure is normal . Another group of patients will have normal acid exposure but have symptoms that temporally relate to either acid or nonacid reflux events. There are even less data on how to deal with a positive symptom association when the patient is on reflux medications. Personally, I do not consider reflux proven based on symptom association in patients with normal acid exposure whether on- or off-reflux medications. It is important to remember that both the SI and SAP are best characterized when used to measure acid events and not nearly so well accepted when measuring nonacid events identified with impedance testing, especially on medication.
Are there medical approaches to reflux-related regurgitation beyond acid suppression?
In 2005, the first American College of Gastroenterology guidelines for treatment of GERD  stated:
“The pathogenesis of GERD is related to defects in esophagogastric motility. Ideal pharmacological therapy would correct these defects, making suppression of normal amounts of gastric acid unnecessary. Results with the available drugs have been disappointing.”
Unfortunately, little has changed in the past 20 years, although there have been a number of studies looking at nonacid-suppressing methods of reflux/regurgitation control. For example, although not directly targeting regurgitation, a trial of baclofen demonstrated an improvement of both acid and nonacid reflux events measured during impedance/pH monitoring . An additional trial suggested an improvement in postprandial retrograde events in patients with rumination or supragastric belching . Lesogaberan is a GABA receptor agonist under study as a gastrointestinal agent. In a trial of adding this medication to PPI therapy, there was an improvement in both heartburn and regurgitation . Many other agents have been studied with the goal of reducing reflux without necessarily blocking acid or as an “add-on” therapy in patients with refractory reflux including arbaclofen placarbil (a prodrug with perhaps a better side effect profile) . Alginates are suggested to form a pH-neutral “raft” in the proximal stomach and hence prevent reflux. In a randomized trial of patients on once-daily PPI with ongoing symptoms, alginate improved the severity and frequency of heartburn but also decreased the frequency of regurgitation . European formulations have a higher concentration of alginate making comparisons difficult. Despite a large investment from pharmaceutical companies and many clinical studies, there are really no safe and effective prokinetic agents widely available for GERD patients.
How does reflux-related regurgitation that is refractory to PPI therapy respond to reflux surgery?
There have been several studies looking at the prevalence of regurgitation before and after laparoscopic fundoplication . There were two studies reporting baseline prevalence of 71.4% and 93.3%, which decreased to 3.6% and 13.3%, respectively [24, 25]. A longer term study suggested some recurrence of regurgitation over time reporting 29.1% at 10 years . Some patients with abnormal motility may experience regurgitation and blame it on GERD when they are really experiencing esophageal stasis, especially after fundoplication. An additional small study compared patients who responded to PPI to those who did not and who eventually underwent a fundoplication . Regurgitation resolved in 96% of the PPI responders and in 84% of the PPI nonresponders. It seems to be clear that refractory regurgitation responds to reflux surgery in well-selected patients.
There have been several nonsurgical, endoscopic methods developed to help control reflux. In a 5-year study of radiofrequency application to the LES, all reflux symptoms including regurgitation were improved over baseline . A study of 696 patients who had troublesome regurgitation despite daily PPI use were randomized to either omeprazole of transoral esophageal fundoplication (TF). The regurgitation was eliminated in 67% after TF compared to 45% on omeprazole . The newly developed magnetic sphincter device showed outstanding control of regurgitation with moderate or severe regurgitation present prior to implant in 57% of patients but only in 1.2% at 5 years postimplant . Fundoplication remains the gold standard, but some of these other approaches may, in time, prove to be an alternative in patients requiring mechanical control of esophageal reflux.
Overview of the Symptom of Regurgitation
Regurgitation is a symptom most often described as the effortless return of material from the stomach to esophagus. It can simply be the feeling of material coming into the chest but also can come all the way into the mouth and is often accompanied by a sour or burning sensation. There remains some controversy in even defining the symptom. The Montreal Conference was an attempt to provide clear definitions in GERD. There was nearly a 50–50 split among international specialists; one contingent defined regurgitation as gastric contents entering the mouth or hypopharynx evidenced by a sour or bitter taste, and the other contingent included in the definition the perception of gastric contents entering the esophagus, without requirement of a taste sensation .
As above noted, it is most common in gastroesophageal reflux disease with a prevalence of up to 80% in some series. Despite that association, it is not perfectly specific for GERD, especially when not accompanied by heartburn. If food, swallowed fluid, or both do not empty from the esophagus, usually related to esophageal motility disorders such as achalasia, a very similar symptom can occur. The type of material can help distinguish (bland and often containing food with achalasia) in some but not all cases. Another possibility is rumination. This was briefly discussed above, but probably deserves additional comment. Traditionally, this was thought to be associated with delayed or impaired mental development, but recently has been reported more frequently in older patients without cognitive issues . The Rome Criteria for rumination requires persistent or recurrent regurgitation of recently ingested food into the mouth with subsequent spitting or remastication and swallowing that is not preceded by retching. Supportive criteria include lack of preceding nausea, cessation of the process when material becomes acidic, and finding of a “pleasant taste” in the regurgitant material . Given that achalasia can present similarly, testing to exclude that diagnosis and perhaps to look for manometric signs of rumination is critical. It is important to understand that ambulatory pH testing can be misleading in these patients since rumination and reflux can look very similar.