Patients Presenting With Reflux Symptoms - Whom to Test and Whom to Treat?
Article information
Abstract
Gastroesophageal reflux disease (GERD) is a complex condition with diverse clinical presentations, ranging from typical heartburn and regurgitation symptoms to extraesophageal manifestations and alarm symptoms. Determining which patients should be tested first versus those who should receive empirical treatment remains a key clinical challenge. If not recently performed, initial patient testing, commonly involving upper endoscopy, is recommended for patients presenting with alarm or refractory symptoms and for those at high risk for Barrett’s esophagus. Additionally, testing should be prioritized for patients with underlying comorbidities, such as scleroderma, increased body mass index, or a suspected large hiatal hernia. Older patients with atypical symptom presentations and those with extraesophageal symptoms or signs, especially in the absence of typical GERD symptoms, should also be referred for endoscopy if recent endoscopic results are not available. In contrast, patients with typical GERD symptoms in the absence of alarm features and those with extraesophageal symptoms accompanied by typical GERD symptoms could begin empirical treatment with a proton pump inhibitor (PPI) or potassium competitive acid blocker (PCAB). For individuals without alarm symptoms who do not respond to once-daily PPI therapy, escalation to twice-daily PPI therapy or switching to a PCAB, without further testing, is appropriate. Overall, an individualized approach is recommended, with patient presentation guiding the decision to test or treat first.
INTRODUCTION
Gastroesophageal reflux disease (GERD) is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications [1,2]. GERD is a worldwide problem, with an estimated global prevalence as high as 13.3% and more than 20%–30% of US adults reporting symptoms at least weekly [3,4]. Although heartburn and regurgitation are considered typical symptoms, a broad range of manifestations may be associated with GERD, including coughing, globus sensation, wheezing, posterior laryngitis, dental erosions, and idiopathic pulmonary fibrosis. GERD-related symptoms can be broadly categorized as esophageal or extraesophageal [2,5]. The phenotypic presentation of GERD varies, with 60%–70% of patients presenting with non-erosive reflux disease, 30% with erosive esophagitis (EE), and 5%–12% with Barrett’s esophagus (BE) [6].
The frequency, duration, and severity of symptoms, either alone or in combination, do not reliably indicate the phenotypic presentation of GERD or EE severity. Similarly, these symptoms are not helpful for differentiating between GERD phenotypes and functional esophageal disorders, particularly those in which heartburn is the primary symptom [7-9]. Additionally, disorders that coincide with GERD, such as scleroderma, mixed connective tissue disorder, and diabetes mellitus, may lead to additional symptoms or may accentuate typical GERD symptoms.
However, diagnosing GERD remains challenging. In most situations, at least a 50% reduction in symptom frequency during empirical treatment with a proton pump inhibitor (PPI) is sufficient to make a diagnosis in most patients [10]; however, this standard approach may not be suitable for all patients. Patients who do not respond to optimal PPI therapy, present with extraesophageal manifestations, or exhibit alarm symptoms require additional diagnostic testing. Many tests currently available for diagnosing GERD are costly, invasive, and not always readily available [11]. Recent studies and guidelines have shifted the GERD management paradigm from a universal approach to one that is more individualized, integrating behavioral, pharmacological, endoscopic, and surgical options. Similarly, the diagnostic approach should be personalized by incorporating each patient’s individual clinical characteristics, prior treatment responses, and risk factors.
This review summarizes the current approaches for managing patients with GERD, focusing on whom to test and whom to treat.
WHOM TO TEST?
Alarm symptoms
Patients presenting with GERD symptoms and alarm features should undergo initial diagnostic endoscopy to evaluate their symptoms. Alarm symptoms include dysphagia, odynophagia, gastrointestinal bleeding, anorexia, weight loss, and persistent vomiting; their presence may indicate more serious underlying conditions that require immediate and thorough investigation (Table 1). This management approach is important to rule out malignancies, strictures, or other significant esophageal mucosal pathologies that could cause these symptoms. Both the American Gastroenterological Association (AGA) and the American College of Gastroenterology (ACG) support this recommendation, emphasizing the need for endoscopic testing in patients with alarm symptoms [12,13]. In a retrospective analysis of approximately 30000 patients with dysphagia who underwent endoscopy, more than 50% had important clinical findings, including esophageal strictures (the most common finding, 40.8%), followed by ulcers, Schatzki’s ring, esophageal food impaction, and suspected malignancies [14]. Therefore, endoscopy is prioritized over empirical PPI therapy for these patients.
GERD alarm symptoms that obligate immediate endoscopy
Barrett’s esophagus
Patients with an increased risk for BE also require upfront testing. BE is the only known precursor of esophageal adenocarcinoma, a cancer that has exhibited a rapidly increasing incidence over recent decades [15]. The risk group is comprised of individuals with chronic (≥5 years) GERD symptoms and three or more of the following risk factors: male sex, age over 50 years, White race, tobacco smoking, obesity, or a family history of BE or esophageal adenocarcinoma [16]. A systematic review and meta-analysis demonstrated that the prevalence of BE in individuals with GERD and one or more of the aforementioned risk factors is as high as 12.2%. Furthermore, a positive linear relationship was observed, with each additional risk factor increasing BE prevalence by 1.2%, supporting the rationale for targeted BE screening in high-risk populations [17]. Moreover, a recent retrospective analysis of over 350000 patients from two national databases evaluated the prevalence of BE after a negative initial endoscopy. The prevalence of BE on repeat endoscopy was 1.7%–3.4%, which was higher in patients with multiple risk factors, suggesting that most cases were likely missed initially. The authors emphasized the importance of high-quality initial endoscopic examinations [18]. In summary, patients with GERD symptoms and BE risk factors should undergo endoscopy rather than empirical PPI therapy. This approach ensures an accurate diagnosis and appropriate management of BE [12,13].
Underlying comorbidities
The presence of underlying comorbidities, such as morbid obesity or a suspected hiatal hernia, requires therapeutic interventions such as bariatric surgery or hernia repair with anti-reflux surgery, respectively. 13 In both clinical scenarios, pre-surgical endoscopic evaluation and, if unremarkable, reflux testing and esophageal manometry are recommended. Roux-en-Y gastric bypass is increasingly regarded as the anti-reflux surgery of choice for obese patients (body mass index >35 kg/m2), serving both as a primary anti-reflux procedure and as an effective weight reduction intervention [19].
Other comorbidities, including mixed connective tissue disorder and scleroderma, warrant consideration for upfront testing because of the potential for significant esophageal mucosal abnormality and esophageal motility disorders. Testing includes endoscopy and esophageal manometry. These patients commonly present with moderate to severe EE or BE [20].
Refractory GERD
When twice daily empirical PPI treatment results in a partial or non response in patients with GERD and typical reflux symptoms after at least 8 weeks of treatment, further testing may be necessary. Ultimately, there are several reasons justifying the decision for testing: to establish a GERD diagnosis if one was not previously made, evaluate for complications, assess treatment response, and determine the underlying mechanism(s) for the lack of treatment response [21]. A recent study involving 366 patients referred to gastrointestinal clinics for heartburn unresponsive to PPIs found that, after extensive evaluation, only 78 patients (21%) had heartburn that was truly refractory to PPIs and related to reflux [22].
The initial test should be an upper endoscopy, if not recently performed. If negative, the next test should be reflux testing, followed by esophageal manometry.
Patients of advanced age
Special consideration is required when managing GERD in individuals of advanced age. Concomitant comorbidities, such as diabetes mellitus, neurological disorders, and polypharmacy, may lead to advanced EE and GERD complications [23]. Although the diagnostic approach for older patients largely mirrors that for younger individuals, atypical symptoms, such as dysphagia, respiratory complaints, and vomiting, are more prevalent than typical symptoms, particularly in patients with severe EE [24]. Endoscopy plays a pivotal role in older patients, as this population is more likely to present with GERD-related mucosal abnormalities [23]. The diagnostic yield of upper endoscopy is significantly higher in this demographic than it is in younger patients, with an estimated 50% of older patients showing clinically significant findings [25]. Therefore, empirical treatment should not be automatically initiated in this patient population; instead, an individualized approach should be considered, often including additional diagnostic evaluations prior to therapy initiation.
Atypical/extra-esophageal symptoms
The diagnostic accuracy of PPI testing in patients with atypical/extraesophageal symptoms and signs, such as chronic cough, wheezing, hoarseness, sinusitis, laryngitis, globus, nausea, and epigastric pain, has not been well studied. Empirical PPI trials, on the other hand, show no or minimal superiority over placebo in patients with suspected extraesophageal reflux-related symptoms, largely because 50%–60% of these patients do not have underlying GERD and, thus, do not respond to anti-reflux therapy [26]. A prospective, double-blind study used dual-probe pH monitoring to compare the diagnostic accuracy of empirical PPI therapy with pantoprazole (40 mg, twice daily) for four months in patients with laryngopharyngeal reflux (LPR); the authors reported a 92.5% sensitivity and a 14% specificity [27]. Again, this finding corresponded with the fact that acid is an uncommon cause of LPR in the absence of typical reflux symptoms or endoscopic features of reflux esophagitis. De Bortoli et al. [28] found that only 12.2% of patients with LPR symptoms had abnormal esophageal acid exposure times, and these patients predominantly exhibited classic GERD and LPR symptoms. Moreover, cost-effectiveness studies have shown a preference for early reflux monitoring over empirical PPI trials when evaluating extra-esophageal reflux-related symptoms, indicating cost savings with upfront testing [29,30]. For example, the initial physiological evaluation of pH impedance in patients with LPR is estimated to cost an average of $1897, compared with $3033 for empirical twice-daily PPI therapy [29].
Chronic cough has also been linked to GERD, but recent studies and systematic reviews indicate that PPIs are generally ineffective for treating chronic cough in most patients, reflecting a significantly lower likelihood of acid reflux being a direct cause [10,31,32]. A randomized controlled trial involving 40 individuals with chronic cough but without heartburn demonstrated no improvement in cough-related quality of life or symptoms following PPI treatment [32]. However, the role of PPIs in asthma treatment remains unclear. Although one study showed improved nocturnal asthma symptoms in patients receiving twice-daily PPI treatment, others failed to demonstrate any effectiveness [33-35].
Given the aforementioned findings, the current guidelines of the AGA, ACG, and recent Lyon Consensus recommend upfront endoscopy and, if negative reflux testing (e.g., pH impedance monitoring), over relying solely on empirical PPI therapy for diagnosing GERD in patients presenting with only extraesophageal manifestations and lacking typical GERD symptoms (e.g., heartburn and regurgitation) [2,5].
For extra-esophageal symptoms having a low likelihood of reflux as the underlying cause, such as cough or asthma, an initial evaluation by a pulmonologist may be warranted. In contrast, patients with symptoms such as globus or hoarseness may require an initial laryngoscopy. Conditions such as supragastric belching and rumination should ideally be identified using pH impedance testing and esophageal manometry, respectively, and managed with behavioral therapy [10].
WHOM TO TREAT?
For patients presenting with typical reflux symptoms, such as heartburn and regurgitation, but without alarm symptoms, an empirical 4- to 8-week trial of a single-dose PPI or the PPI test (double-dose PPI over a period of one or two weeks) is considered appropriate for patient management (Table 2) [12]. The PPI test is considered to be a highly sensitive, simple, readily available, and cost-effective tool for diagnosing GERD. However, its accuracy varies depending on the presenting symptoms. Ghoneim et al. [36] found that the test has a high pooled sensitivity (79%; 95% confidence interval [CI], 72%–84%), but only an adequate specificity (45%; 95% CI, 40%–49%) in patients with heartburn as the predominant symptom. However, the PPI test demonstrates high sensitivity (79%) and specificity (79%) in patients with chest pain due to GERD.
Whom to test and whom to treat when patients present with GERD-like symptoms
For patients who present with typical GERD symptoms in the absence of alarm features, but fail to respond to once-daily PPI treatment, escalation to twice-daily PPI dosing or switching to a more potent acid-suppressive agent, such as potassium competitive acid blockers (PCABs), is recommended. If patients respond to twice-daily PPI, their dosage should be tapered to the lowest effective dose that controls their symptoms [13]. Additionally, for patients who present with atypical or extra-esophageal symptoms or signs suspected to be due to GERD in addition to typical GERD symptoms but in the absence of alarm manifestations, empirical treatment with a twice-daily PPI is warranted; subsequent tapering to the lowest effective dosage can be attempted.
Yadlapati and Pandolfino [20] suggested a stepwise systematic framework for phenotyping patients that was designed to optimize diagnostic accuracy while minimizing both risks and costs. The initial step involves characterizing the patient’s symptom profile as typical or extraesophageal, characterizing any alarm symptoms, and assessing the response to PPI therapy. This initial assessment is crucial for determining the suitability of empirical PPI treatment and identifying patients who may require upfront esophageal testing.
CONCLUSIONS
The effective management of GERD requires a personalized approach that balances empiric treatment with timely diagnostic evaluation. Patients presenting with typical GERD symptoms, such as heartburn and regurgitation, but without alarm symptoms, can be managed empirically with a PPI or PCAB. Patients with typical GERD symptoms who do not respond to once-daily PPI therapy and who do not have alarm symptoms can be escalated to twice-daily PPI therapy or switched to a PCAB. Upfront treatment with a double-dose PPI may also be considered for patients presenting with both atypical/extraesophageal symptoms/signs and classical GERD symptoms.
Patients with alarm symptoms; at risk for BE; having comorbidities (e.g., morbid obesity and scleroderma), refractory GERD, advanced age; and with atypical or extraesophageal symptoms without classic GERD features should undergo diagnostic testing before treatment. Upper endoscopy is the most commonly recommended initial diagnostic test in such cases, followed by reflux testing and esophageal manometry.
Notes
Availability of Data and Material
All data generated or analyzed during the study are included in this published article.
Conflicts of Interest
Ronnie Fass, a contributing editor of the Korean Journal of Helicobacter and Upper Gastrointestinal Research, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest.
Funding Statement
None
Acknowledgements
None
Authors’ Contribution
Conceptualization: Ronnie Fass. Data curation: Noy Lapidot Alon, Tomas Navarro Rodriguez. Formal analysis: Noy Lapidot Alon, Tomas Navarro Rodriguez. Investigation: Noy Lapidot Alon, Tomas Navarro Rodriguez. Methodology: all authors. Project administration: Ronnie Fass. Resources: Noy Lapidot Alon, Tomas Navarro Rodriguez. Software: Noy Lapidot Alon, Tomas Navarro Rodriguez. Supervision: Ronnie Fass. Validation: all authors. Visualization: Noy Lapidot Alon, Tomas Navarro Rodriguez. Writing—original draft: all authors. Writing—review & editing: all authors. Approval of final manuscript: all authors.