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

Abstract

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.

Introduction

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.

Prevalence of Functional Dyspepsia/NERD

It is thought that this functional dyspepsia/NERD spectrum may account for up to 70% of GERD patients in the community.[10,11] This clinical entity has a considerable socioeconomic impact, with £250 million spent annually by UK general practitioners in the treatment of upper gastrointestinal disease, including GERD.[12] It is very difficult to estimate the true prevalence of functional dyspepsia/NERD due to the lack of uniformity in the definitions used. El-Serag and Talley[13] found that the prevalence of uninvestigated dyspepsia ranged from 10% to 40% when they used a more inclusive definition of dyspepsia which incorporated heartburn and regurgitation; when the definition was restricted to upper abdominal pain alone, the prevalence fell to 5% to 12%. This study also demonstrated that dyspepsia is, indeed, a worldwide problem and that the majority of patients with uninvestigated dyspepsia actually fall into the functional dyspepsia group.

It is estimated that there are no visible esophageal erosions in over 50% of patients who present with reflux symptoms in primary care, thus illustrating the importance of NERD and the need to make the correct diagnosis to avoid unnecessary treatment and minimize costly investigations.[14,15] Twenty percent of the US population reports weekly heartburn or regurgitation symptoms.[16] It is apparent from these and other studies that, irrespective of the definitions used, both functional dyspepsia and NERD are interrelated and commonly encountered conditions in the community that have an impact on quality of life equivalent to complicated GERD, and therefore warrant appropriate treatment and investigation.[17,18]

Functional Dyspepsia and NERD: Clinical Connections

To fully understand the overlap between functional dyspepsia and NERD, we must first look at the pathophysiology of these interrelated conditions. Many potential mechanisms have been purported to play a role in symptom generation and are listed in Table 1 .[19]

Table 1.

Pathophysiology of Functional Dyspepsia: Proposed Mechanisms and Related Symptoms

Mechanism	Associated Symptoms
Delayed gastric emptying	Postprandial fullness, nausea, vomiting
Hypersensitivity to gastric distension	Epigastric pain, belching, weight loss
Impaired accommodation	Early satiety, weight loss
Helicobacter pylori infection	Unknown
Duodenal lipid hypersensitivity	Nausea
Duodenal acid hypersensitivity	Nausea
Unsuppressed phasic contractility	Bloating
Esophageal acid sensitivity	Heartburn
Longitudinal esophageal contractions	Chest pain

Visceral hypersensitivity plays a major role in both functional dyspepsia and NERD and is thought to be present in 30% to 40% of cases.[4] Studies have demonstrated a sensitivity not only to mechanical distension in some of these patients but also to the introduction of certain substances, such as acid and lipid solution. Samsom and colleagues[20] have previously shown that patients with functional dyspepsia are more sensitive to the introduction of exogenous acid into the duodenum. The development of the gastric barostat allowed investigators to accurately measure gastric tone and sensory responses to distension.[21] Using the gastric barostat, several studies have clearly demonstrated increased sensitivity to distension, in functional dyspepsia, at lower distending pressures relative to normal healthy controls.[22–24] Mearin and colleagues[25] nicely demonstrated that this hypersensitivity was truly visceral by showing no difference between dyspeptic patients and healthy controls in terms of somatosensory responses. However, a subsequent study by Bouin and colleagues[26] looked at somatic sensation by hand immersion in cold water, and found that patients with functional gastrointestinal disorders perceived pain earlier and had a lower pain tolerance than did normal controls.[26] This would seem to contradict the study by Mearin's group, suggesting that there is not just a visceral problem but that perhaps it is part of a more generalized sensory dysfunction.

The majority of functional dyspepsia patients describe their symptoms as being most prominent after food ingestion. Accordingly, studies have shown that about 60% to 70% of patients with functional dyspepsia are hypersensitive to an infusion of lipid into the duodenum.[27,28] It would also appear that hypersensitivity is nutrient-specific, as the intraduodenal infusion of an emulsion of long-chain triglycerides induced fullness, nausea, and bloating in patients with functional dyspepsia, whereas an infusion of glucose did not.[29] It is clear from these studies and others that small intestinal “sensing” of certain nutrients and fat, in particular, as well as the motor response in the foregut to their instillation, may play a role in the induction of symptoms in functional dyspepsia.

Hypersensitivity is also seen in NERD patients in response to both intraesophageal balloon dilatation and acid. Classic GERD is typically defined by endoscopic features and an abnormal 24-hour pH study; but in NERD, not only will endoscopy be macroscopically normal, but also between 33% and 50% of patients will demonstrate normal acid exposure over 24 hours.[7,30] However, there is evidence that abnormalities exist at the microscopic level in NERD patients, including dilated intercellular spaces on electron microscopy, which may account for symptom generation.[31,32]

NERD patients have been subclassified into 3 types on the basis of the results of the 24-hour pH study, as illustrated in Table 2 .[33] Type 1 NERD consists of patients with a normal endoscopy but who demonstrate abnormal acid exposure time on pH studies in a manner similar to those with erosive esophagitis.[34] One study estimated that 45% of their NERD population fell into this category.[34] Type 2 comprises those patients with a normal acid exposure time but in whom symptoms and reflux events are significantly correlated, suggesting acid hypersensitivity; this has been referred to as “the sensitive esophagus.”[34–36] Last, Type 3 NERD includes those patients with typical reflux symptoms but normal pH studies and no correlation between symptoms and acid exposure; this is also referred to as “functional heartburn.”[37]

Table 2.

NERD Subgroups

Result of pH Study	Type 1	Type 2	Type 3
Acid exposure	Abnormal	Normal	Normal
Symptom-reflux correlation	Positive	Positive	Negative

The recent Rome III criteria for functional esophageal disorders includes this latter group of patients.[38] It has been estimated that functional heartburn represents less than 10% of patients with heartburn who present to gastroenterologists.[34] Although the terminology continues to evolve in this area of functional gastrointestinal disorders, there is certainly overlap between the second and third NERD subgroups and functional dyspepsia. Recent data also suggest a dysfunction in the upper stomach in NERD patients.[39,40] This is probably due to the fact that the lower esophageal sphincter and the gastric fundus are intimately involved in the induction of transient lower esophageal sphincter relaxations, which precipitate most episodes of reflux. Some studies report that up to 50% of NERD patients have dysmotility/dyspepsia symptoms. Disturbances in gut motility, like delayed gastric emptying, have also been described in both NERD and functional dyspepsia patients and may explain the relative ineffectiveness of proton-pump inhibitor (PPI) therapy in some of these patients.

Clinical Implications

The overlap between these 2 disease spectra has implications for the investigation and management strategies for each condition. Should we investigate all patients who present with heartburn and/or dyspepsia by endoscopy, which is invasive and time-consuming, or is a therapeutic trial with acid-suppressive agents adequate? By definition, a negative endoscopy is needed to diagnose the NERD patient – but what about the patient with functional dyspepsia? Is a “test-and-treat” regimen adequate in this cohort? Such questions need to be addressed in well-powered randomized controlled trials. It is now common practice to try a therapeutic trial (also known as the PPI test) with acid-suppression therapy in most GERD patients, which may in turn help to identify the functional heartburn patient.[41] Acid-suppression is, overall, less effective in NERD than in erosive esophagitis, largely a consequence of the failure to segregate functional heartburn.[42,43] However, it has been shown that some “overlap patients” will respond to PPI therapy, especially the functional dyspepsia patient with heartburn.[44–46]

Given the relative ineffectiveness of PPI therapy in functional heartburn in particular and in NERD in general, it was hoped that prokinetic therapy would offer some potential therapeutic benefit. However, in one large European study, less than half of patients with NERD maintained remission on cisapride (first-generation promotility agent; cisapride was withdrawn from the US market in July 2000 because of safety concerns).[47] More recently, hopes were raised by a positive phase 2 study in functional dyspepsia with another prokinetic agent, itopride,[48] only to be dashed by 2 subsequent – and, as yet, unpublished –negative phase 3 studies. In terms of surgical intervention, clinicians need to be extremely cautious in considering referral for fundoplication. The best results from surgery are seen in those patients with typical reflux symptoms, an abnormal pH study, and a good response to acid-suppression therapy.[49,50] In reality, this accounts for a small proportion of NERD patients. Also, NERD patients with prominent dyspeptic symptoms may become debilitated with bloating post fundoplication due to the accentuation of impaired gastric accommodation.[39,51] Finally, delayed gastric emptying may be further impaired in the event of vagal injury.[52] It appears evident from these observations that strict criteria need to be adhered to in the selection of surgical candidates for antireflux procedures and that this procedure should be avoided in those with overlap with functional dyspepsia in particular.

Conclusion

Precise definitions are needed to distinguish both functional dyspepsia and NERD patients, and future trials should include strict criteria to avoid unnecessary confusion. To date, clinicians have relied on conventional methods of diagnosis, such as endoscopy and 24-hour pH monitoring, but there is as yet no “gold standard” test in this setting. Perhaps the advent of chromoendoscopy and high-resolution endoscopy may further clinicians' ability to make the correct diagnosis by identifying more subtle changes indicative of GERD and esophagitis. As we come to understand the pathophysiology of these complex disorders, novel agents (eg, visceral analgesics) may offer therapeutic hope.