Mini-Reviews and PerspectivesPersistent Reflux Symptoms in the Proton Pump Inhibitor Era: The Changing Face of Gastroesophageal Reflux Disease
Section snippets
Definition and Epidemiology
Incomplete response of classic GERD symptoms, such as heartburn and regurgitation, to PPI therapy is common. A recent American Gastroenterological Association survey of >1000 subjects receiving PPI therapy for GERD symptoms demonstrated that 38% reported residual symptoms, and that more than half of those with residual symptoms took additional medication to control symptoms, most commonly over-the-counter antacids (47%).4 A systematic review of symptom control in trials of PPI therapy for GERD
Differential Diagnosis of Residual Reflux Symptoms on PPI
When patients have symptoms of ongoing reflux despite maximal PPI therapy, the main clinical question is: Are these symptoms related to gastroesophageal reflux? There is a broad differential diagnosis to consider, and potential etiologies may be gastrointestinal (GI) or non-GI related. The GI etiologies can be esophageal or nonesophageal, and the former may be reflux or non-reflux related. There are 3 major categories of reflux-related causes. First is reflux with ongoing acid exposure.
Mechanisms of Persistent Reflux Symptoms
The putative mechanisms of PPI-refractory GERD symptoms are illustrated in Figure 1. Similar to the differential diagnosis for symptoms, the mechanisms can be either reflux or non-reflux related.
Diagnostic Evaluation of Persistent Symptoms
For patients with esophageal reflux symptoms that persist on PPI therapy, the goal is to determine whether there is reflux disease, what the mechanism might be, and if there is not reflux disease, to perform other appropriate evaluation (Figure 2). After consideration of serious non-GI pathology and ensuring correct medication dosing, upper endoscopy is performed. It is important to recognize the yield of this procedure for structural disease is low, with only 0.2% of patients having esophageal
Therapeutic Options
As noted, the escalation of PPI therapy beyond BID dosing is of unproven utility, and the vast majority of GERD subjects on BID dosing normalize esophageal acid exposures. Although early work suggested that the addition of nighttime H2 receptor antagonists was beneficial,74 follow-up studies demonstrated early tolerance limiting utility,75 and routine administration of nighttime H2 blocker is not recommended.8 Several classes of medications have been proposed as adjunct therapy for subjects
Conclusion
Persistent reflux symptoms in the face of PPI therapy are common in subjects treated for GERD, and most subjects will not demonstrate pathologically elevated acid exposures. Multiple pathophysiologic mechanisms have been proposed to account for these persistent symptoms. The diagnostic evaluation of subjects with persistent reflux symptoms while on PPIs revolves around excluding alternative diagnoses and isolating the likely mechanism(s) of symptoms. A variety of therapeutic modalities are
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Cited by (33)
Proton Pump Inhibitor–Refractory Gastroesophageal Reflux Disease
2019, Medical Clinics of North AmericaCitation Excerpt :Reduced esophageal clearance can occur with impaired esophageal peristalsis, in the setting of a hiatal hernia with re-refluxing of bolus, and impaired salivation.21 Barrier function of the esophageal mucosa is maintained by cell-to-cell junctions and works to prevent toxic substances from compromising the mucosal integrity.22 Biopsies in patients with erosive and nonerosive reflux disease show evidence of microscopic esophagitis: necrosis, erosions, eosinophilic or neutrophilic infiltrate, basal cell hyperplasia, elongation of papillae, or dilation of intercellular spaces.23
The nonsteroidal anti-inflammatory drug diclofenac reduces acid-induced heartburn symptoms in healthy volunteers
2015, Clinical Gastroenterology and HepatologyBenign surgical diseases of the gastro-oesophageal junction
2014, Surgery (United Kingdom)Citation Excerpt :Persistent dysphagia to solid food occurs in less than 5% of patients at 3 months after surgery. Conversely, patients with oesophageal dysmotility secondary to reflux damage or outflow obstruction due to a hiatus hernia often report improved swallowing following anti-reflux surgery.5 If severe or persistent symptoms are present then clinical assessment should be with barium swallow to look for excessive hiatal tightness or fibrosis, or malposition or slippage of the wrap.
Comparison of gastroesophageal reflux disease questionnaire and multichannel intraluminal impedance pH monitoring in identifying patients with chronic cough responsive to antireflux therapy
2014, ChestCitation Excerpt :Microaspiration and esophageal-tracheobronchial reflex are the main mechanisms underlying GERC.1, 5 Proton pump inhibitors can reduce the acidity and volume of refluxate and even decrease reflux episodes when combined with prokinetic agents.21 Even for cough caused by weakly acidic reflux, which accounts for the majority of nonacid reflux,22 a mild increase in the pH value of refluxate might result in a significant blockade of acid signal transduction in a hypersensitive esophagus followed by cough resolution.23
Chronic cough: An update
2013, Mayo Clinic ProceedingsCitation Excerpt :Using a new technology that detects acid and nonacid refluxate, the 24-hour esophageal impedance pH probe found chronic cough related to acid reflux (45%), nonacid reflux (24%), and esophageal hypersensitivity (8%).121 Failure of the empirical PPI trial in chronic cough may, therefore, be due to several reasons.122 First, PPIs have no effect on the frequency or duration of reflux episodes.123
Conflicts of interest The authors disclose the following: Nicholas J. Shaheen receives research funding from AstraZeneca, BARRX Medical, CSA Medical, Oncoscope Procter & Gamble, and Takeda, and is a consultant for AstraZeneca, CSA Medical, Oncoscope, and Takeda. Evan S. Dellon receives investigator-initiated research funding from AstraZeneca.