“In the United States, approximately 20% of adults regularly have symptoms of gastroesophageal reflux disease (GERD), and annual costs for managing GERD exceed $12 billion. Patients with heartburn, the cardinal symptom of GERD, report reduced work productivity and significant impairments in health-related quality of life. Proton-pump inhibitors (PPIs) are highly effective for healing reflux esophagitis but less effective for eliminating GERD symptoms, which persist in some 30% of patients treated with PPIs. Only 58% of patients taking prescription PPIs for chronic heartburn report complete satisfaction with this treatment, and “PPI-refractory GERD” is the most common reason for GERD-related referrals to gastroenterologists.
Five major mechanisms might underlie PPI-refractory heartburn: first, abnormal acid reflux persists despite PPI therapy; second, there is reflux hypersensitivity, in which esophageal exposure to acid is normal but “physiologic” reflux episodes (acidic or nonacidic) evoke heartburn; third, heartburn is caused by esophageal disorders other than GERD (e.g., achalasia); fourth, heartburn is caused by extraesophageal disorders (e.g., heart disease); or fifth, heartburn is functional (i.e., not due to GERD or any other identifiable histopathologic, motility, or structural abnormality). The frequency with which these mechanisms underlie PPI-refractory heartburn is not clear, and distinguishing among them requires systematic evaluation that includes endoscopy with esophageal biopsy, esophageal manometry, and esophageal multichannel intraluminal impedance (MII)–pH monitoring. MII-pH monitoring measures reflux episodes (acidic according to pH, and nonacidic according to MII) and their association with heartburn episodes.
[..] Among 366 patients enrolled in our trial of medical and surgical treatments for PPI-refractory heartburn, systematic evaluation revealed that GERD underlay truly PPI-refractory heartburn in only a minority of patients. In 42 patients referred because of “PPI-refractory” heartburn, heartburn was relieved during a standardized, 2-week trial of omeprazole twice daily. A systematic evaluation showed that GERD was not the likely cause of heartburn for an additional 122 patients — 99 received a diagnosis of functional heartburn and 23 received a diagnosis of a non-GERD organic disorder. Only 78 patients completed the full assessment and were found to have GERD that was truly unresponsive to twice-daily PPIs. In that highly selected group, the incidence of treatment success with laparoscopic Nissen fundoplication at 1 year (67%) was significantly superior to that with active medical treatment (28%) or control medical treatment (12%).
In our trial, a substantial minority of patients who were referred to gastroenterology clinics with “PPI-refractory” heartburn got relief when prescribed omeprazole twice daily with explicit instruction on how to take it properly. There are two likely explanations as to why some previously PPI-refractory patients had a response to this standardized PPI trial. First, trial patients were given explicit instructions to take omeprazole 30 minutes before meals. This is important because PPIs bind only to gastric proton pumps that are actively secreting acid. Fewer than 10% of those pumps are active during fasting, whereas approximately 70% are active when stimulated by meals. Consequently, PPIs are most effective when taken before meals. Second, patients taking PPIs other than omeprazole at trial entry were switched to omeprazole. Relative potencies of different PPIs vary widely, and individual patients can exhibit considerable variability in response to different PPIs.
This trial highlights the critical importance of systematic evaluation, similar to that recommended by Gyawali and Fass, for managing the care of patients with PPI-refractory heartburn. Many patients would not complete this rigorous evaluation, and among those who did, the cause of heartburn in most of them was not GERD. Furthermore, no demographic or clinical characteristics distinguished patients with reflux-related heartburn from those with functional heartburn, those whose heartburn responded to omeprazole taken properly, and those who would not complete diagnostic evaluation. Although coexisting psychological conditions are common in patients with functional gastrointestinal disorders, we found no significant differences in PHQ-9 depression and GAD-7 anxiety scores between patients who received a diagnosis of functional heartburn and those who received a diagnosis of reflux-related, PPI-refractory heartburn, with both groups having mean scores in the “moderate” range (i.e., 7 to 10).”