Key points

Introduction

Gastroesophageal reflux disease (GERD) is a very common clinical problem. Heartburn or acid regurgitation is experienced on a weekly basis by nearly 20% of the US population, with an annual prevalence of up to 59%. GERD may be diagnosed by symptom assessment through patient history or GERD questionnaires, response to a trial of proton pump inhibitors (PPIs), findings of reflux-related esophageal mucosal damage by endoscopy, or by establishing the presence of pathologic reflux on prolonged ambulatory monitoring with pH or impedance-pH. In routine clinical practice, GERD is frequently diagnosed by symptom presentation along with a good response to a PPI trial. Although this constitutes a simple and reasonable approach in the appropriate setting (eg, primary care of uncomplicated patients), it is important to bear in mind its limitations.

In addition to careful history-taking for typical symptoms of GERD, validated questionnaires are available to measure specific symptoms and GERD-related quality of life scales. These instruments can be helpful but they generally have similar specificity and sensitivity compared with clinical examination by a gastroenterologist. Therefore, they are most commonly used in clinical trials.

Upper endoscopy is indicated for patients with alarm features such as dysphagia, bleeding, or weight loss, and in patients with typical symptoms that do not respond appropriately to PPI therapy. The finding of erosive esophagitis on endoscopy provides robust evidence of GERD, but this lesion is present in only one-third of untreated patients and it is uncommon in those that are in treatment with a PPI. Random biopsies to document GERD in patients with normal endoscopy are not advised because of the limited diagnostic capabilities of conventional histology for this purpose.

When endoscopy is negative in patients with an uncertain diagnosis of GERD or a suboptimal response to PPI, further work up involves objective quantification of gastroesophageal reflux. This can be accomplished through pH monitoring (catheter-based or wireless), which can establish whether a pathologic amount of acid reflux is present and may provide insight regarding the association between reflux episodes and reported symptoms. Impedance-pH monitoring enables measurement of not only acid, but also nonacid (with a pH >4) reflux episodes. Nonacid reflux may be important in patients with PPI-refractory symptoms. Objective documentation of GERD by endoscopy or reflux monitoring is mandatory before antireflux surgery. Of note, barium esophagram and esophageal manometry cannot establish whether GERD is present and are not useful to diagnose it. However, these tests, especially manometry, may enable a diagnosis of non-GERD causes of esophageal symptoms in PPI-refractory patients (ie, achalasia or rumination). It is important to keep in mind the possibility of non-GERD causes (eg, achalasia, eosinophilic esophagitis [EoE], or a functional disorder) in PPI-refractory patients. In this context, endoscopy and reflux monitoring can be valuable tools to exclude GERD. The pros and cons of diagnostic modalities for GERD are summarized in Table 1 . This article focuses primarily on patients with typical symptoms (heartburn or regurgitation) and discusses different modalities for the work up of GERD. A section summarizing the diagnostic approach for PPI-refractory symptoms, a common clinical problem, is also included.

Introduction

Gastroesophageal reflux disease (GERD) is a very common clinical problem. Heartburn or acid regurgitation is experienced on a weekly basis by nearly 20% of the US population, with an annual prevalence of up to 59%. GERD may be diagnosed by symptom assessment through patient history or GERD questionnaires, response to a trial of proton pump inhibitors (PPIs), findings of reflux-related esophageal mucosal damage by endoscopy, or by establishing the presence of pathologic reflux on prolonged ambulatory monitoring with pH or impedance-pH. In routine clinical practice, GERD is frequently diagnosed by symptom presentation along with a good response to a PPI trial. Although this constitutes a simple and reasonable approach in the appropriate setting (eg, primary care of uncomplicated patients), it is important to bear in mind its limitations.

In addition to careful history-taking for typical symptoms of GERD, validated questionnaires are available to measure specific symptoms and GERD-related quality of life scales. These instruments can be helpful but they generally have similar specificity and sensitivity compared with clinical examination by a gastroenterologist. Therefore, they are most commonly used in clinical trials.

Upper endoscopy is indicated for patients with alarm features such as dysphagia, bleeding, or weight loss, and in patients with typical symptoms that do not respond appropriately to PPI therapy. The finding of erosive esophagitis on endoscopy provides robust evidence of GERD, but this lesion is present in only one-third of untreated patients and it is uncommon in those that are in treatment with a PPI. Random biopsies to document GERD in patients with normal endoscopy are not advised because of the limited diagnostic capabilities of conventional histology for this purpose.

When endoscopy is negative in patients with an uncertain diagnosis of GERD or a suboptimal response to PPI, further work up involves objective quantification of gastroesophageal reflux. This can be accomplished through pH monitoring (catheter-based or wireless), which can establish whether a pathologic amount of acid reflux is present and may provide insight regarding the association between reflux episodes and reported symptoms. Impedance-pH monitoring enables measurement of not only acid, but also nonacid (with a pH >4) reflux episodes. Nonacid reflux may be important in patients with PPI-refractory symptoms. Objective documentation of GERD by endoscopy or reflux monitoring is mandatory before antireflux surgery. Of note, barium esophagram and esophageal manometry cannot establish whether GERD is present and are not useful to diagnose it. However, these tests, especially manometry, may enable a diagnosis of non-GERD causes of esophageal symptoms in PPI-refractory patients (ie, achalasia or rumination). It is important to keep in mind the possibility of non-GERD causes (eg, achalasia, eosinophilic esophagitis [EoE], or a functional disorder) in PPI-refractory patients. In this context, endoscopy and reflux monitoring can be valuable tools to exclude GERD. The pros and cons of diagnostic modalities for GERD are summarized in Table 1 . This article focuses primarily on patients with typical symptoms (heartburn or regurgitation) and discusses different modalities for the work up of GERD. A section summarizing the diagnostic approach for PPI-refractory symptoms, a common clinical problem, is also included.

Diagnosing GERD by symptoms and response to acid suppression

Heartburn and regurgitation are considered the most reliable symptoms for making a history-based diagnosis of GERD but are far from perfect in this respect. In fact, these symptoms actually have variable sensitivity and specificity for diagnosing GERD. Although heartburn is the most typical symptom of GERD, patients with heartburn represent a heterogeneous group; even if many or most of them have GERD, others may experience heartburn as a result of other esophageal disorders such as EoE or achalasia. Furthermore, some patients may have no organic cause for this symptom and are thus diagnosed with functional heartburn, one of the recognized functional gastrointestinal disorders. GERD patients may also present with dysphagia, one of the alarm symptoms that warrants endoscopic evaluation to exclude a complication including malignancy. However, other potential causes for dysphagia must not be ignored. Chest pain may also be reported by GERD patients but this symptom requires thorough evaluation for cardiac disease before GERD is considered.

Recently, the spectrum of clinical presentations attributed to GERD has expanded beyond the typical esophageal symptoms of heartburn and regurgitation and now includes various extraesophageal manifestations, including asthma, chronic cough, and laryngitis. However, a causal relationship between reflux and these extraesophageal presentations has been difficult to prove and these atypical symptoms frequently have multifactorial causes in which gastroesophageal reflux may be a cofactor instead of a cause. Extraesophageal syndromes rarely occur in isolation without concomitant typical symptoms of GERD.

A variety of validated questionnaires have been developed for GERD, including specific symptom scales, quality of life scales, and those which combine the two. A comprehensive discussion of these instruments is outside the scope of this article. Although these instruments may be helpful, they have similar specificity and sensitivity to a clinical examination by a gastroenterologist and are usually reserved for screening large numbers of patients by personnel who are not specialists or as part of clinical trials.

Although the limitations of heartburn and regurgitation for making a diagnosis of GERD should be recognized, it is not necessary to conduct a diagnostic evaluation in all patients with typical symptoms and no alarm features. For these patients, a short trial of acid suppression with a PPI represents a noninvasive, simple, and reasonable option for supporting a diagnosis of GERD. If the patient has a clear response to therapy, it can be assumed that GERD is present. That is not to say that the PPI test is without shortcomings. The manner in which this test is administered is not standardized, with differing PPI doses (once vs twice daily), variable duration of treatment (from 1 to 4 weeks), and different definitions of a positive response to PPI (either partial or complete). Moreover, a meta-analysis of several studies that evaluated the diagnostic capability of a short course of PPI compared with other diagnostic interventions, found a sensitivity of 78% and specificity of 54% for the PPI test.