Gastroesophageal reflux disease (GERD) is a chronic condition related to the reflux of gastric contents into the esophagus leading to bothersome symptoms (classically heartburn and regurgitation).
In the United States it is the most prevalent gastrointestinal disorder. In addition to a significant compromise in quality of life, potential complications of GERD include stricture, dysphagia, esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma.
Acid production plays a critical role in the development of heartburn. Proton pump inhibitors (PPIs) decrease acid production and are the mainstay of GERD treatment.
However, a significant percentage of patients with GERD symptoms will not respond to PPIs. It has been estimated that approximately 30% of patients with a suspected diagnosis of GERD will experience a lack of symptomatic improvement, either partially or completely, despite PPI treatment.
Refractory symptoms of GERD are a challenging but important issue with potentially costly diagnosis, treatment, and management. However, it is necessary to delineate refractory symptoms of GERD (e.g., heartburn or regurgitation) that may not be related to GERD. This article focuses on recognizing refractory GERD and refractory GERD symptoms, differential diagnosis, and the role of diagnostic tests and therapeutic options.
| Definition |
GERD can be subdivided into erosive reflux disease or non-erosive reflux disease (NERD) based on endoscopic findings. Both types exhibit variable success with PPI therapy. Patients with NERD do not have findings of esophagitis on endoscopy, but have typical symptoms of GERD, with a generally high esophageal acid exposure time on pH monitoring.
In one study, patients with NERD, representing up to 70% of the GERD population, had a lower effective response rate to once-daily PPI therapy at 4 weeks compared to patients with erosive esophagitis. (37% vs. 56%, respectively), with a similar study showing comparable results.
Patients who have a normal acid exposure time but a positive symptom index (SI) or probability of symptom association (PAS) are classified as reflux hypersensitive . If heartburn remains the predominant symptom, but IS and SBP are normal, patients are classified as having functional heartburn according to the Rome IV criteria.
Both functional disorders of the esophagus are the etiology of persistent symptoms in refractory GERD in up to 90% of patients. There is often a typical GERD concomitant with these 2 functional disorders of the esophagus.
According to one study, in 75% of patients with GERD refractory to once-daily PPI treatment, 62.5% had functional heartburn and 12.5% had reflux hypersensitivity. Given this prevalence of overlapping functional esophageal disease, treatments should be directed toward neuromodulation, psychological therapy, and adjunctive therapy as opposed to increased antireflux medications or surgical or endoscopic interventions.
Further complicating the definition of refractory GERD are the differential responses of typical GERD symptoms to PPI therapy. Heartburn is more responsive than regurgitation to PPI treatment, and regurgitation likely plays an important role in symptomatic GERD.
Furthermore, expert opinion varies on whether failure to a standard dose of once-daily PPI therapy or having a partial lack of response to twice-daily dosing should be considered a treatment failure.
For the purposes of this article, refractory GERD will be defined as an inadequate symptom response after at least 8 weeks of twice-daily PPI treatment. Once refractory GERD is suspected, the differential diagnosis of these symptoms should be explored.
| Differential diagnosis of refractory gastroesophageal reflux disease |
Experts estimate that more than two-thirds of patients referred to a gastroenterologist with GERD symptoms refractory to PPI therapy do not have GERD . One study showed that up to 63% of refractory GERD patients report symptoms that cannot be correlated with GERD. The differential diagnosis of refractory GERD can be divided according to etiology.
> Insufficient acid suppression or increased reflux
• Proton pump inhibitor compliance and timing . Two observational studies have found that only 53.8% and 67.7% of patients, respectively, adhered to their PPI prescription at least 80% of the time.
Medication timing has also been shown to be a major problem with PPI therapy. The optimal time is 30 to 60 minutes before meals. One study found that only 46% of patients received PPIs at the appropriate time.
Another study reported that 36% of physicians give no or inappropriate instructions to patients regarding the timing of PPI therapy. A cost-effective and management first step includes a discussion about medication adherence along with education about appropriate timing.
• Cytochrome P450 2C19 polymorphism . PPIs are significantly metabolized by the liver enzyme cytochrome P450 2C19 (CYP2C19). There are three possible genotypes for this enzyme: rapid metabolizers, intermediate metabolizers, and slow metabolizers.
Studies indicate that the response rate of PPIs varies between the 3 groups, with 52.2% of extensive metabolizers, 56.7% of intermediate metabolizers, and 61.3% of poor metabolizers responding effectively.
Furthermore, patients who were extensive metabolizers were 66% more likely to experience refractory symptoms on standard-dose PPIs compared to poor metabolizers. Almost all studies have been conducted with once-daily PPI therapy.
However, one study found that after 8 weeks of therapy for intermediate and extensive metabolizers, twice-daily PPI therapy was associated with a significantly greater sustained symptomatic response compared to once-daily therapy, with no differences. in the poor metabolizer group, suggesting that PPI metabolism may play a role in refractory GERD.
• Weakly acidic or non-acidic reflux. Two multivariate analyzes postulated that proximally spreading reflux episodes with a mixed liquid and gas composition are significantly associated with symptoms regardless of reflux pH.
Weakly acidic reflux is defined as any reflux event in which the esophageal pH drops by 1 unit or more but remains less than 4, as measured by pH impedance. The mechanism by which weakly acidic or non-acidic reflux can cause symptoms is not fully understood, but is believed to be a combination of mechanical distention and/or the contents of the reflux.
• Nocturnal acid reflux. It is extremely common, experienced by up to 80% of patients receiving twice-daily PPI therapy. One study demonstrated the effectiveness of histamine-2 receptor antagonists (H2RA) at night along with 20 mg of omeprazole twice daily in almost completely eliminating it.
However, another study showed similar symptom severity scores regardless of whether a patient was treated with ranitidine despite reduction in nocturnal reflux. Currently, there is insufficient evidence that it alone is an important cause of refractory GERD.
• Omitted gastroesophageal reflux disease. Current tests for GERD have limitations and can lead to a missed diagnosis. Catheter testing can be uncomfortable and may limit patients’ typical eating patterns, leading to uncharacteristic acid reflux patterns and increasing the potential for false-negative results. Although ambulatory pH monitoring has been shown to reduce patient discomfort, false negative results have been reported up to 30% of the time.
• Acid bag. An acid pocket refers to a postprandial buildup of strong gastric acid near the gastroesophageal junction that does not mix with food. A pocket of acid can migrate into the esophagus shortly after eating, causing possible reflux symptoms. The use of PPIs can reduce the size of this pouch and increase gastric pH. However, it is not known how much the acid pocket contributes to refractory GERD.
• Duodenogastroesophageal reflux. Duodenogastroesophageal reflux (RDGE) refers to the reflux of duodenal contents through the stomach and into the esophagus. Bile acids may play a role in refractory GERD through weakly acidic or non-acidic reflux. More severe forms of GERD have been shown to have both acid and bile reflux content compared to less severe forms.
> Functional disorders
Functional gastrointestinal disorders are defined as symptomatic disorders without an obvious organic etiology.
The Rome IV criteria define functional heartburn as episodic substernal pain for at least 3 months without evidence of reflux or underlying motility disorder, as shown by upper endoscopy testing and normal pH, with a negative association between symptoms and reflux events. It is estimated that about 60% of patients classified as having refractory GERD would qualify as having functional heartburn.
The underlying mechanism of functional heartburn is not fully understood, but is thought to be related in part to reflux hypersensitivity . This hypersensitivity is defined as an increased esophageal sensitivity to various chemical, mechanical, electrical and temperature stimuli, which may be related to the sensitization of the enteric nervous system to acid through dilated intracellular spaces.
Patients with refractory GERD have been shown to have increased pain sensitivity to both mechanical and electrical stimulation. Both are amplified by psychological stress. Significant life stress predicted increased overall heartburn severity and symptoms.
> Alternative diagnoses unrelated to gastroesophageal reflux disease
There are several non-GERD conditions that should be considered for a patient with PPI-refractory symptoms, including Zollinger-Ellison syndrome, autoimmune skin conditions, and pill-induced esophagitis. The following disorders that can cause heartburn and/or regurgitation deserve special attention.
• Eosinophilic esophagitis.
Eosinophilic esophagitis (EE) is an important clinical consideration in any patient with refractory GERD.
Although GERD is a potential etiology and PPI use may improve EE, it is likely that there is also an allergenic or food allergen component mediated by a release of cytokines from Th2 cells.
The diagnosis is made with a biopsy, which reveals more than 15 eosinophils per high-power field. Differentiating this condition from GERD can be challenging, as they share symptomatology, both may be associated with eosinophilia, and both may respond to PPI therapy. Given the increased incidence of EoE, the American College of Gastroenterology currently recommends endoscopy with esophageal biopsy for all patients with refractory GERD to rule out EoE.
• Achalasia . Achalasia is a rare disorder of esophageal dysmotility characterized by aperistalsis, a hypertensive lower esophageal sphincter, and inability of the lower esophageal sphincter to relax.
The patient often complains of dysphagia to solids and liquids, regurgitation, and sometimes heartburn. Some patients report only symptoms of heartburn refractory to PPI therapy, in which the heartburn is actually food and fluid retained above the lower esophageal sphincter. This diagnosis can be made with upper gastrointestinal endoscopy and can be confirmed by esophageal manometry.
• Gastroparesis . Gastroparesis is characterized by a delay in gastric emptying into the small intestine leading to increased reflux. Symptoms typically include epigastric pain, early satiety, postprandial bloating, and nausea.
One study revealed that patients with refractory GERD with erosive esophagitis were more likely to have delayed gastric emptying compared to patients with erosive esophagitis but no symptoms.
| Assessment |
If there are any warning symptoms (dysphagia, weight loss, iron deficiency anemia, bleeding), the American College of Gastroenterology recommends that these patients first undergo an upper endoscopy to rule out Barrett’s esophagus, stricture, and malignancy, among others. other conditions.
When a patient presents with typical GERD symptoms such as heartburn and reflux without alarm symptoms, it is reasonable to empirically start single-dose PPI treatment in the morning before breakfast.
Clinicians should also look for lifestyle modifications in their patients to lose weight, stop smoking, elevate the head of the bed, and avoid the right lateral decubitus position. If these interventions fail, it is important to verify patient compliance with PPI therapy and ensure appropriate timing of PPI administration.
If these interventions continue to fail, patients should be started on twice-daily PPI therapy. If patients remain symptomatic after 8 weeks, they would be classified as having refractory GERD and should proceed with diagnostic testing with endoscopy.
> Upper digestive endoscopy
Endoscopy allows visualization to determine the presence of esophagitis, which helps the doctor with the differential diagnosis. It also allows the exclusion of other disorders. Careful initial treatment allows for an appropriate diagnostic approach for the patient with refractory GERD.
In the absence of obvious esophagitis, biopsies of the esophagus may be useful, especially when there is concomitant dysphagia to help rule out Barrett’s esophagus, lichen planus, or EoE. Particular attention should be paid to a hiatal hernia and a possible wrinkled lower esophageal sphincter during endoscopy to evaluate achalasia or possible dysmotility. Evaluating the stomach for retained food can also help identify the potential for gastroparesis.
> Reflux test
When there is a report of heartburn or regurgitation without esophagitis evident on endoscopy and persistent symptoms despite PPI therapy, pH testing should be completed to determine the role of acid reflux.
Whether using a catheter pH test or a wireless pH test placed during endoscopy, the pH test should be performed without antireflux medications to evaluate the native state of gastric acid production.
When it can be done, the wireless pH capsule is preferred as it offers 48 to 96 hours of pH monitoring with a proposed reduction of the transnasal catheter that can limit eating habits and activities, which can lead to missed diagnosis.
> Impedance-pH test
For patients with GERD known by previous endoscopy or pH testing with breakthrough symptoms, multichannel intraluminal impedance (MII) pH testing should be considered to evaluate the role of weakly acidic or non-acidic content.
Given the established diagnosis of GERD, this testing should be completed with PPI therapy to determine the role of breakthrough reflux. Of patients who undergo MII testing, 25% will have a positive SI or SAP for non-acid reflux, triggering their refractory GERD. For patients with extraesophageal manifestations, the presence of heartburn, asthma, and a body mass index greater than 25 were found to have a high probability of reflux, and these patients were recommended to undergo MII testing during therapy.
> High resolution esophageal manometry
Although not a first-line test for refractory GERD, high-resolution esophageal manometry has a role in defining GERD mimics, including achalasia, rumination syndrome, and supragastric belching. Heartburn is observed in up to 35% of patients with achalasia and should therefore feature prominently in the differential diagnosis of the possible etiology of refractory GERD.
> Gastric emptying test
For patients with suspected gastroparesis, a gastric emptying test should be performed to help confirm this diagnosis. If confirmed, increasing the PPI dose is unlikely to be helpful, but dietary modifications and possible prokinetics may help improve gastric motility, which may decrease reflux symptoms.
| Medical therapy for partial response to proton pump inhibitor |
> Proton pump inhibitors
For patients with abnormal endoscopy, pH testing, or impedance testing consistent with reflux as the etiology of symptoms, PPIs are the mainstay of therapy. Particular attention should be paid to patients with a possible CYP2C19 isoenzyme leading to rapid metabolism. Although this test is not currently cost-effective, one strategy is to use medications that are not exclusively metabolized by CYP2C19 (i.e., rabeprazole or esomeprazole). For patients with partial response to PPI therapy, transition to CYP2C19-independent PPIs is a reasonable step.
> Histamine-2 receptor antagonists
H2RAs can be administered to patients who respond to PPIs and have nocturnal symptoms. Given their effectiveness despite food intake, H2RAs serve as an option to reduce nocturnal symptoms.
> Antacids with alginate
Alginate antacids act by forming a mechanical barrier between gastric contents and the lower esophageal sphincter when exposed to gastric acid. With this ability to form a barrier, alginate antacids have found utility in controlling postprandial heartburn and regurgitation. For patients with partial response to PPIs, the addition of antacids with alginate serves as a useful adjunct.
> Neuromodulators
For patients with reflux hypersensitivity or functional heartburn, medications aimed at decreasing central nervous system pain processing pathways may help with these refractory symptoms.
Both tricyclic antidepressants and selective serotonin reuptake inhibitors can decrease esophageal sensitivity. In a study comparing placebo, fluoxetine, and omeprazole for refractory GERD, fluoxetine reduced the incidence of heartburn over placebo or omeprazole.
| Endoscopic Therapy for Refractory Gastroesophageal Reflux Disease |
> Transoral incisionless fundoplication (TIF)
As a method to endoscopically wrap part of the fundus around the gastroesophageal junction, TIF has become the most studied endoscopic method. In the TEMPO study, TIF was found to be superior to high-dose PPI therapy in 60 patients defined as partial responders to PPI therapy followed at 6 months for the primary outcome of improvement in regurgitation.
> Radiofrequency ablation
Data from case series have shown improvement of symptoms in patients with refractory GERD. In a prospective analysis, radiofrequency energy delivery was performed and the primary outcome showed normalization of GERD health-related quality of life in 70% or more of patients at 10 years.
These findings are limited by the lack of controlled data and the lack of physiological evidence on changes in reflux. Currently, there is insufficient evidence to advocate radiofrequency ablation in patients with refractory GERD. More studies are needed to determine its role in treatment and long-term effectiveness.
| Surgical therapy for partial response to proton pump inhibitor |
> Laparoscopic fundoplication
Nissen fundoplication is an important tool in the management of typical GERD symptoms that respond to PPI therapy. Predictors of response to antireflux surgeries include at least 50% symptom improvement with PPI therapy, compliance with antireflux medications, presence of typical GERD symptoms, and objective findings of acid reflux.
Poor response to PPI treatment is an independent risk factor for lack of response to antireflux surgery. Without the aforementioned response metrics, care should be taken in selecting patients with refractory GERD for antireflux surgery.
In a recent multicenter, randomized controlled trial, patients with refractory reflux-induced GERD were randomized to 3 arms. Laparoscopic fundoplication plus omeprazole (67%) was superior (as measured by the GERD-related quality of life scale) to active medical treatment with baclofen plus omeprazole (28%) and omeprazole alone (12%.
> Increase of the magnetic sphincter
Minimally invasive antireflux surgeries have offered new modalities for antireflux therapy, including magnetic sphincter augmentation, which is placed around the lower esophageal sphincter and allows bolus passage and the ability to belch as an advantage over surgical fundoplication.
Limitations of its widespread use in refractory GERD include lack of prospective or randomized data and lack of statistical power for a primary outcome of improvement in physiologic data, not just patient-reported outcomes.
| Summary |
Refractory GERD is a common disorder seen in both primary care and gastroenterology clinics. When symptoms occur, a complete history can help determine red flag symptoms requiring endoscopy, non-GERD pathology, or functional esophageal disease.
When symptoms are persistent, invasive testing is usually performed to evaluate objective signs of reflux and rule out non-GERD etiologies of regurgitation or heartburn symptoms.
Testing reflux parameters using traditional pH testing or MII testing should be considered to evaluate reflux or weakly acidic or non-acidic content. With symptoms predictive of partial response to PPI therapy, objective findings of reflux, possible mechanical hiatal hernia, and medication compliance, surgical fundoplication has a role in the management of pathological reflux with objective findings. Minimally invasive surgery and endoscopic options have not yet demonstrated long-term management of pH parameters.
Importantly, the overwhelming prevalence of functional disorders of the esophagus with GERD should not be underestimated and, in these situations, therapy aimed at neuromodulation, as well as behavioral therapy, is more likely to have long-term efficacy and avoid the need of unnecessary surgeries or an increase in antireflux drugs.
