Functional Dyspepsia and Nonerosive Reflux Disease: Clinical Interactions and Their Implications

John Keohane, MB, MRCPI; Eamonn M.M. Quigley, MD, FRCP, FACP, FACG

In This Article

Abstract and Introduction

Functional dyspepsia or nonulcer dyspepsia, and nonerosive reflux disease (NERD) or endoscopy-negative reflux disease, are common reasons for referral to a gastroenterologist. Although there is much confusion with regard to definition, recent research would suggest that these 2 conditions are linked and may represent components in the spectrum of the same disease entity, in terms of both symptoms and pathophysiology. Several theories have been proposed regarding the etiology of these disorders, including acid exposure, visceral hypersensitivity, impaired fundal accommodation, delayed gastric emptying, and Helicobacter pylori infection.

In an era when the incidence of gastric cancer and peptic ulcer disease are decreasing, it is the functional gastrointestinal disorders such as functional dyspepsia and irritable bowel syndrome that have come to the forefront. Functional dyspepsia and gastroesophageal reflux disease (GERD) now account for a majority of upper gastrointestinal symptoms.[1,2] However, robust clinical definitions for dyspepsia remain evasive, and this term and its various qualifiers have been interpreted differently by both physician and patient alike for years. Despite attempts by numerous committees and consensus groups to agree on a uniform definition, clinical trials continue to use different diagnostic terminology, rendering the interpretation of data challenging. The Rome II committee defined functional dyspepsia as the presence of abdominal pain or discomfort centered in the epigastrium and present for at least 12 weeks over the last 12 months, which cannot be explained by upper gastrointestinal investigation.[3] The more recent Rome III definition[4] requires symptoms to be present for the last 3 months, with symptom onset at least 6 months before diagnosis. In a major shift in emphasis, it also proposed that functional dyspepsia comprises at least 2 distinct subgroups: the postprandial distress syndrome, which features postprandial fullness and early satiety; and the epigastric pain syndrome, which features a more constant and less meal-related pain syndrome.[4] Patients with prominent heartburn are excluded from both Rome definitions. The Rome committee contends that as heartburn and dyspepsia arise from separate organs, the esophagus and the stomach, respectively, these entities should be separated in clinical definitions.[4] In our opinion, such a clear separation is often impossible on clinical grounds given the overlap that exists between these disorders; however, it is clearly evident that dyspeptic patients with predominant heartburn are those most likely to respond to acid suppression, thereby supporting the value of identifying the predominant symptom in a given patient.[5]

What has led to such a dramatic shift in definition between the Rome II and Rome III criteria? Such variations, within the same essential framework, are reflective of basic difficulties in the clinical categorization of "dyspeptic" symptoms. Symptoms are poor predictors of pathology: Moayyedi and colleagues,[6] for example, demonstrated that neither the clinical impression of a primary care physician or specialist, nor patient input into a computer model, was of real value in distinguishing between organic and functional dyspepsia. Clinical trials conducted in patient populations with uninvestigated dyspepsia are likely, therefore, to be heterogeneous and may comprise some patients with GERD and peptic ulcers and others with functional dyspepsia. Thus, clarity of definition is mandatory: Uninvestigated dyspepsia needs to be clearly differentiated from functional dyspepsia and dyspepsia of organic causation.

NERD, like functional dyspepsia, by definition requires normal endoscopy findings, hence its alternative name: "endoscopy-negative" reflux disease. It has been defined "as the presence of typical symptoms of GERD caused by intra-esophageal acid, in the absence of visible esophageal mucosal injury at endoscopy."[7] However, the criteria for inclusion of patients in NERD clinical trials have also been far from uniform. Patients with NERD clearly do not comprise a homogeneous population and include not only patients whose symptoms are clearly acid-related but also others who, despite presenting with the most classic symptoms of GERD, namely heartburn, fail to demonstrate any response to intense acid-suppression therapy. Furthermore, given the well-recognized overlap in symptomatology between patients with NERD and functional dyspepsia, one can reasonably ask, Where in the disease spectrum does symptomatic GERD end and functional dyspepsia begin?[8] The recently published Montreal classification has made some headway in addressing this question by proposing a more global and all-encompassing definition of GERD as follows: "GERD is a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications."[9] The consensus group defined NERD as the presence of troublesome reflux-associated symptoms and the absence of mucosal breaks at endoscopy. All experts agree that NERD is an increasingly recognized problem whose symptoms are as severe as those associated with erosive reflux disease and that it has a significant impact on the quality of life of affected patients.[10] In this review, we will examine interactions between GERD and functional dyspepsia and explore their implications for the evaluation and management of these common disorders.

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