Diagnosis and Management of Reflux Refractory to PPIs
Diagnosis and Management of Reflux Refractory to PPIs
Approximately a third of patients with suspected gastro-oesophageal reflux disease are resistant or partial responders to proton pump inhibitors (PPIs). Many of these patients do not have gastro-oesophageal reflux disease, but suffer from functional heartburn or dyspepsia. The potential mechanisms underlying failure of PPI treatment in patients with reflux-related symptoms include persistence of isolated or mixed acid, weakly acidic, bile or gas reflux, impaired oesophageal mucosal integrity, chemical or mechanical hypersensitivity to refluxates and psychological comorbidity. After thorough clinical evaluation and failure of empirical changes in PPI dose regime, diagnostic investigations include endoscopy and reflux monitoring with pH or pH-impedance monitoring. If symptoms are clearly related to persistent reflux, baclofen, antireflux surgery or pain modulators can be considered. If not, pain modulators are the only currently available therapy.
Acid suppression with proton pump inhibitors (PPIs) is the mainstay of therapy for gastro-oesophageal reflux disease (GORD). It is known that resolution of oesophageal mucosal inflammation is more likely to occur than resolution of symptoms. It has been estimated that between 10% and 40% of the patients with GORD fail to respond symptomatically, either partially or completely, to a standard dose PPI. Failure of the PPI treatment to resolve reflux symptoms has become one the most common presentations of GORD in gastrointestinal (GI) clinical practice. As GORD is one of the most prevalent chronic disorders in the Western world, even a small proportion of GORD patients becoming therapy-resistant encompasses a substantial part of the work load of general practitioners, internists and gastroenterologists.
Most of the patients with reflux symptoms who are not responsive to PPIs originate from the non-erosive reflux disease (NERD) phenotype ( Box 1 ), primarily due to their relative large size in the GORD patient population (up to 70%) and low response rate to PPI once daily (response pooled rate 36%). In addition, it appears that NERD patients with normal or only mildly abnormal oesophageal acid exposure, who account for a significant portion of the NERD group, exhibit a relatively lower symptom response rate to PPI once daily as compared with the other patients with NERD. Functional heartburn ( Box 1 ) patients with normal endoscopy and normal pH testing exhibit the lowest symptom response rate to PPI.
Patients with GORD often have functional digestive disorders that may also influence the response to therapy. The association of heartburn with dyspeptic symptoms including epigastric pain, bloating, early satiety and nausea/vomiting is present in approximately a third of GORD patients. Dyspeptic symptoms contribute significantly to the decrement in health-related quality of life related to GORD and are less likely to respond to antireflux therapy.
GORD is a costly disease, resulting in consultation, referral and treatment costs of nearly $10 billion annually in the USA and PPI failure represents an expensive clinical problem due to repeated utilisation of healthcare resources such as clinic visits, diagnostic tests and prescription medications. It can also be a significant financial burden on society through the cost of long-term reduced work productivity and increased work absenteeism.
The abovementioned prevalence and relevance of PPI-refractory reflux symptoms outline the need for new treatment options for symptomatic patients taking PPI therapy.
This review will first examine and update the definition, potential pathophysiological mechanisms, clinical evaluation and current or developing therapeutic options for patients with reflux symptoms incompletely responsive to PPI therapy; in a second part, an algorithm for management and treatment will be proposed.
Abstract and Introduction
Abstract
Approximately a third of patients with suspected gastro-oesophageal reflux disease are resistant or partial responders to proton pump inhibitors (PPIs). Many of these patients do not have gastro-oesophageal reflux disease, but suffer from functional heartburn or dyspepsia. The potential mechanisms underlying failure of PPI treatment in patients with reflux-related symptoms include persistence of isolated or mixed acid, weakly acidic, bile or gas reflux, impaired oesophageal mucosal integrity, chemical or mechanical hypersensitivity to refluxates and psychological comorbidity. After thorough clinical evaluation and failure of empirical changes in PPI dose regime, diagnostic investigations include endoscopy and reflux monitoring with pH or pH-impedance monitoring. If symptoms are clearly related to persistent reflux, baclofen, antireflux surgery or pain modulators can be considered. If not, pain modulators are the only currently available therapy.
Introduction
Acid suppression with proton pump inhibitors (PPIs) is the mainstay of therapy for gastro-oesophageal reflux disease (GORD). It is known that resolution of oesophageal mucosal inflammation is more likely to occur than resolution of symptoms. It has been estimated that between 10% and 40% of the patients with GORD fail to respond symptomatically, either partially or completely, to a standard dose PPI. Failure of the PPI treatment to resolve reflux symptoms has become one the most common presentations of GORD in gastrointestinal (GI) clinical practice. As GORD is one of the most prevalent chronic disorders in the Western world, even a small proportion of GORD patients becoming therapy-resistant encompasses a substantial part of the work load of general practitioners, internists and gastroenterologists.
Most of the patients with reflux symptoms who are not responsive to PPIs originate from the non-erosive reflux disease (NERD) phenotype ( Box 1 ), primarily due to their relative large size in the GORD patient population (up to 70%) and low response rate to PPI once daily (response pooled rate 36%). In addition, it appears that NERD patients with normal or only mildly abnormal oesophageal acid exposure, who account for a significant portion of the NERD group, exhibit a relatively lower symptom response rate to PPI once daily as compared with the other patients with NERD. Functional heartburn ( Box 1 ) patients with normal endoscopy and normal pH testing exhibit the lowest symptom response rate to PPI.
Patients with GORD often have functional digestive disorders that may also influence the response to therapy. The association of heartburn with dyspeptic symptoms including epigastric pain, bloating, early satiety and nausea/vomiting is present in approximately a third of GORD patients. Dyspeptic symptoms contribute significantly to the decrement in health-related quality of life related to GORD and are less likely to respond to antireflux therapy.
GORD is a costly disease, resulting in consultation, referral and treatment costs of nearly $10 billion annually in the USA and PPI failure represents an expensive clinical problem due to repeated utilisation of healthcare resources such as clinic visits, diagnostic tests and prescription medications. It can also be a significant financial burden on society through the cost of long-term reduced work productivity and increased work absenteeism.
The abovementioned prevalence and relevance of PPI-refractory reflux symptoms outline the need for new treatment options for symptomatic patients taking PPI therapy.
This review will first examine and update the definition, potential pathophysiological mechanisms, clinical evaluation and current or developing therapeutic options for patients with reflux symptoms incompletely responsive to PPI therapy; in a second part, an algorithm for management and treatment will be proposed.
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