Functional dyspepsia (FD) and non-erosive reflux disease (NERD): overlapping or discrete entities?

Best Practice & Research Clinical Gastroenterology Vol. 18, No. 4, pp. 695–706, 2004 doi:10.1016/j.bpg.2004.04.004 available online at http://www.sciencedirect.com

6 Functional dyspepsia (FD) and non-erosive reflux disease (NERD): overlapping or discrete entities? Eamonn M.M. Quigley*

MD, FRCP, FACP, FACG, FRCPI

Professor of Medicine and Human Physiology, Head of the Medical School National University of Ireland Department of Medicine, Cork University Hospital, Clinical Sciences Building, Cork, Ireland

As the incidence of both gastric cancer and peptic ulcer disease have declined, that of gastrooesophageal reflux disease (GORD) and non-ulcer, or functional dyspepsia (FD) have reached virtually epidemic proportions. As we come to appreciate the expression of these disorders in the community, the real spectrum of each disease has become evident. FD and non-erosive reflux disease (NERD), the most prevalent manifestation of GORD, frequently overlap. Where then does GORD end and FD begin? Is it realistic, or even clinically relevant, to attempt a clear separation between these entities? These are more than issues of mere semantics; therapeutic options may be dictated by the classification of the patient as one or the other. Recent work indicates clearly that NERD is a heterogeneous disorder incorporating some patients who may well harbour subtle manifestations of oesophagitis and others who have entirely normal 24-hour pH studies. These differences may be crucial to the concept of NERD/FD overlap. While evidence in support of this concept is far from complete, it would appear that this overlap is most relevant to those NERD patients who do not exhibit abnormal esophageal acid exposure. These patients truly belong in the spectrum of functional gastrointestinal disorders rather than in GORD; attempts to shoe-horn these individuals into the spectrum of GORD will result in therapeutic disappointment and surgical disaster. Key words: gastro-oesophageal reflux (GORD); non-erosive reflux disease (NERD); dyspepsia; functional dyspepsia (FD); non-ulcer dyspepsia (NUD); proton pump inhibitor (PPI); anti-reflux surgery; oesophageal acid exposure.

Recent decades have witnessed a dramatic change in the pattern of upper gastrointestinal disorders responsible for dyspeptic symptoms in the developed world.1 As gastric cancer and peptic ulcer disease recede, gastro-oesophageal reflux and functional or non-ulcer dyspepsia have emerged as predominant factors in the causation of symptoms referable to the upper gut. The reasons for this seismic shift in * Tel.: þ 353-21-490-1228; Fax: þ 353-21-345-300. E-mail address: [email protected] (E.M.M. Quigley). 1521-6918/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.

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the relative prevalence of these pathologies are beyond the scope of this review; we will focus, instead, on the relationships and interactions between the most common clinical expression of gastro-oesophageal reflux disease (GORD), namely non-erosive reflux disease (NERD), and functional dyspepsia (FD).

WHAT ARE NERD AND FD, WHAT IS THEIR IMPACT? Definitions The term NERD or endoscopy-negative reflux disease (ENRD) has come to be employed to describe those patients with GORD who have either typical or atypical GORD symptoms, yet who do not reveal any mucosal changes on conventional endoscopic examination of the esophagus.1,2 – 5 Alternatively, this GORD subgroup has been referred to as ‘symptomatic GORD; this term may be confusing, as all GORD patients seen in clinical practice are, by definition, ‘symptomatic’, yet may exhibit a wide range of mucosal expressions of acid exposure. In this author’s opinion, the terms NERD or ENRD are more descriptive and less confusing in describing this important GORD subgroup.6 FD is most commonly defined according to the latest iteration of the Rome process, i.e. Rome II, on the basis of ‘pain or discomfort centered in the upper abdomen’ that cannot be readily explained by conventional investigations of the upper GI tract.7 According to Rome II, patients with predominant heartburn should be excluded from consideration, a priori. Why then the fuss about NERD/FD overlap? The problem is that the separation of GORD and FD may not be that easy in the real world. Thus, in clinical practice, GORD and FD symptoms may be readily confused, for a variety of reasons, be they linguistic, cultural or interpretative. For example, how, in the Englishspeaking world, can one confidently distinguish heartburn from ‘indigestion’? Furthermore, it is evident that many patients in the community complain simultaneously of heartburn and dyspepsia; forcing such individuals to decide which is predominant at a given moment in time may be both unrealistic and misleading. The definition of NERD presumes and, indeed, demands the performance of endoscopy; the term symptomatic GORD could be applied to any GORD patient, regardless of endoscopic features, and could be expanded to encompass all those with symptoms, yet who have not been subjected to any form of investigation; i.e. ‘uninvestigated GORD’.6 This very same concept has been applied to the patient with dyspepsia; again endoscopy is a prerequisite for the segregation of FD from the larger population with ‘uninvestigated dyspepsia’.7 While, the apparent dominance of NERD and FD in the developed world, especially among younger populations in the community, may tempt one to equate GORD and dyspepsia with NERD and FD, respectively, this is neither accurate nor desirable and must be eschewed if further confusion is to be avoided in an already fraught area. This review will deal exclusively with NERD and FD; i.e. we will assume that endoscopy has been performed and oesophagitis or its complications and organic causes of dyspepsia have been, thereby, excluded. Prevalence Both NERD and FD are common. Non-erosive or negative-endoscopy reflux disease (NERD) may account for up to 70% of patients with GORD in the community.8 – 10

Functional dyspepsia (FD) and non-erosive reflux disease (NERD): overlapping or discrete entities? 697

Given, firstly, that up to 20% of individuals in the community report weekly heartburn11 and, secondly, a community prevalence of FD also in the range of 20%,12,13 the preeminence of these disorders in the causation of upper GI symptoms can be appreciated. NERD is not a minor issue; its impact on quality of life is at least as impressive as that of esophagitis or complicated GORD.3 – 5,14

THE GORD/FD OVERLAP The evidence for overlap Given the high prevalence rates quoted above for each of these disorders, some degree of overlap between NERD and FD would appear inevitable, by chance alone. However, as illustrated by recent studies demonstrating an increased prevalence of GORD and dyspepsia (X 5 vs. no GORD, in the study by Locke and colleagues11) among patients with dyspepsia and GORD, respectively, the degree of overlap between these conditions is, indeed, greater than would be predicted by chance alone. Furthermore, the age and gender profiles for NERD and FD are similar.12,15 It is noteworthy that, in contrast to GERD, in general, females do predominate in NERD,15 a group who, on the whole, tend to be younger, by a factor of about a decade, than their erosive GERD counterparts. Our current understanding of foregut physiology and pathophysiology would also predict the concurrence of these disorders.16 The physiology of the lower oesophageal sphincter, so fundamental to the pathophysiology of all manifestations of GORD, is intimately related to that of the gastric fundus and cardia.17,18 For example, distension of the upper stomach is the primary trigger of transient lower oesophageal sphincter relaxation (TLOSR); the most important mechanism of reflux in health and disease.19 It is of considerable interest, therefore, that disordered fundic function,20 – 22 and impaired accommodation,23 – 26 in particular, has been invoked, albeit among several other factors,27 in the pathogenesis of FD. Indeed, abnormal accommodation has also been reported in GORD.28 Furthermore, both TLOSR’s and the accommodation reflex are generated and regulated by vago-vagal reflexes.18,19,29 Delayed gastric emptying has been described among some patients with either GORD18 or FD16,30 and visceral hypersensitivity (a hallmark of many functional gastrointestinal disorders, FGID’s31) is evident among many FD patients32 and has been described in a subset of NERD sufferers;33,34 whether the latter represent those NERD patients who also overlap with FD has not been defined. Finally, both disorders owe some of their symptomatology to the effects of acid and pepsin. While these factors are pre-eminent in the causation of GORD it would appear that some FD patients are also prey to the effects of acid and pepsin, whether on the basis of gastric acid ‘sensitivity’35 or impaired duodenal acid clearance.36,37 Clinical trials certainly demonstrate that some FD patients, albeit a minority, will respond to acid suppression.38 – 40 Epidemiological, clinical and pathophysiological data support, therefore, a significant overlap between NERD and FD, in the community. Why, then the haste to separate these disorders? For some, the impetus to discard the term ‘reflux-like’ dyspepsia and to reclassify such patients as GORD has come from studies demonstrating a preferential response to acid suppression among this sub-category of FD, thus suggesting a prominent role for acid exposure among these individuals.38 – 40 Similarly, the failure to demonstrate a response to acid suppression among Chinese patients with

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FD may relate to the low rates of reflux in this population.41 Others, in contrast, point to the instability of such subgroups over time and to a failure to find major differences, in terms of natural history, between patients within the various FD sub-types.42 There is, indeed, a concern regarding the very concept of FD, given the instability of this diagnosis over time. While defining a clear distinction between NERD and FD may be, not only feasible, but important for some NERD patients, it is equally impossible for others. Let me now support this statement with some evidence. Not all NERD is the same; some may ‘overlap’ more than others! It is self-evident that not all GORD is the same;2 it is now becoming clear that NERD is a heterogenous disorder. Thus, endoscopy segregates GORD patients into three groups: 1. Negative-endoscopy reflux disease (NERD). In defining NERD, one must be cognizant of prior therapy; an oesophagus rendered free of oesophagitis, by acidsuppressive therapy, does not constitute NERD. 2. Erosive oesophagitis and related complications, 3. Barrett’s oesophagus and its associated lesions. Similarly, a critical separation, of NERD, into further subgroups can be derived from 24-hour studies of intra-esophageal pH and, in particular, from data on acid exposure and correlations between acid reflux events and symptoms. Accordingly, Fass and colleagues have suggested that NERD may be further defined and sub-classified, based on the results of 24-hour pH recordings, into three distinct groups:4 1. Those with an abnormal acid exposure time (AET). When all NERD patients are studied together as a group, their AET’s are lower than in oesophagits or complicated reflux disease.43 – 45 It is now evident, however, that there are some among those with NERD whose AET’s fall well within the oesophagitis range44; AETpositive patients comprised 45% of a large group of NERD patients in one recent study.44 This sub-group appears to behave, in terms of therapeutic response, in a manner analogous to those with obvious oesophagitis. While conventional histological techniques have not proven valuable in the assessment of endoscopynegative GORD,46 other methodologies show promise. Thus magnification endoscopy can reveal microscopic evidence of mucosal breaks (‘minimal esophagitis’)47,48 and laboratory techniques can identify immune activation49 or disruption of the oesophageal epithelium50 in patients whose mucosa appears entirely normal at the time of examination using conventional endoscopy. It is quite possible that patients identified to harbour subtle evidence of epithelial damage, by one or more of these techniques may correspond to the AET-positive NERD subgroup. 2. Those who demonstrate a normal AET but in whom symptoms and reflux events are significantly correlated (as estimated by some form of symptom index); these individuals have been referred to as ‘the sensitive esophagus’.2,4,33,51,52 3. Those with typical reflux symptoms (i.e. heartburn and acid regurgitation) yet in whom all parameters of the pH study are normal and symptoms correlate poorly with acid exposure.44 These individuals appear highly resistant to acid-suppressive therapy4 and are more likely to demonstrate psychopathology.53 These are

Functional dyspepsia (FD) and non-erosive reflux disease (NERD): overlapping or discrete entities? 699

sometimes referred to as ‘functional heartburn’.54 Terminology here remains confusing; the recently revised ‘Rome’ criteria would incorporate those defined in both categories 2 and 3 in their ‘functional heartburn’ category.54 I contend that it is in this category, also, that overlap with FD assumes clinical significance. Implications for management It is notable that symptom response rates to PPI’s in NERD, while clinically impressive, have been consistently lower than those reported in erosive disease.14,55,56 This would appear counterintuitive; further examination of available data implies that this impaired response may be, in large part, related to the very poor response rates experienced by those with functional heartburn. It has been demonstrated, for example, that response rates, to PPI’s, in NERD are directly correlated to levels of acid exposure;57 given that oesophageal AET’s are, by definition, normal among those with ‘symptomatic heartburn’ a poor symptomatic response to acid expression is predicted for these patients. It is likely that the exclusion of this subgroup may restore PPI response rates, in NERD, to those reported in esophagitis. PPI’s are, indeed, widely employed in NERD; the ability of PPI’s to produce rapid relief of symptoms in GORD58 and even to prevent reflux symptoms from occurring in response to likely provocative stimuli,59 has led to the recommendation of on-demand regimens in NERD.60 – 63 Evidence continues to accrue to support the importance of dyspeptic symptoms in predicting an unfavourable response to both medical and surgical therapy of GERD and NERD, in particular. What is of considerable importance in predicting the response of a given patient with apparent GORD to therapy appears to be where they lie on the continuum between pure GORD at one end and FD at the other. As it has been consistently demonstrated that FD is a disorder where acid suppressing agents have a far smaller impact than in GORD,38 – 41 one can assume that the closer a patient is to the FD end, the less the response to PPI’s. In this way FD/NERD overlap may go a long way towards explaining the observation noted consistently in several studies, as well as in recent reviews and meta-analyses, that acid-suppressive agents, including proton-pump inhibitors, tend to be somewhat less effective in NERD10,52,64 – 70 than in ERD.71,72 This is not to say that NERD patients with dyspepsia do not respond to proton pump inhibitors; indeed, FD patients with heartburn are perhaps those most likely to respond to acid suppression.38 – 40 In theory, prokinetic therapies might offer some theoretical advantages in the overlap patient; to date clinical trials have not fulfilled these expectations and, for now, at least, there are no proven prokinetic therapies available for either mono- or co-therapy in NERD. Many patients with NERD are being considered for, and subjected to, laparoscopic fundoplication. Several recent pieces of evidence indicate that the clinician needs to exert cautious and careful judgment in considering surgical options for the NERD patient. Firstly, it has become clear that the best results from surgery are obtained in those with typical GERD symptoms, an abnormal esophageal pH study and a good symptomatic response to acid suppression;73,74 features not common to all NERD patients. Secondly, it is evident that the NERD patient with prominent dyspeptic features may fare especially poorly and become crippled by gas-bloat and other symptoms post-fundoplication. By definition, therefore, the NERD patient with a negative pH study is eminently unsuitable for any surgical procedure. There are, indeed, potential pathophysiological explanations for these unfortunate occurrences. Impaired gastric accommodation, evident in some with FD, may be further restricted by

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fundoplication.75,76 Delayed gastric emptying, present in some GERD patients at baseline18 and, perhaps, more prevalent among those with NERD, may also be further impaired by fundoplication, if vagal injury occurs.77 Innovative and inventive endoscopists have introduced a third option for the GORD patient; endoscopic therapy. Whether accomplished through the technique of gastroplication,78 the application of radio-frequency energy to the LOS79 or the injection of an inert vinyl alcohol solution into the sphincter80, these approaches all attempt to bolster the gastro-esophageal barrier and/or reduce the frequency of transient lower esophageal sphincter relaxations (TLESR’s).81 For primarily technical reasons, protocols, to date, involving all of these techniques have selected patients without Barrett’s, strictures, advanced grades of oesophagitis or hiatal hernias and are, therefore, likely to prove attractive to the NERD patient, unresponsive to, or reluctant to continue with, medical therapy and fearful of surgery. Experience with any of these procedures remains limited and their impact in NERD and its subgroups remains to be defined. Given the aforementioned experience with functional heartburn patients in relation to fundoplication, one would also advise restraint in subjecting these same patients to endoscopic therapy, pending further data. Can endoscopic features predict therapeutic response in NERD? There is accumulating evidence to implicate the hiatal hernia in predisposing the individual with reflux to oesophagitis and Barrett’s oesophagus;82,83 whether this finding predicts the minority of NERD patients who progress to these more advanced forms of GERD remains to be defined.84 – 91 There is also a suggestion that the presence of an hiatal hernia is predictive of a good response to a surgical approach and currently it precludes such endoscopic treatments as radio-frequency ablation and gastroplasty. Summary As the degree of overlap between NERD and such functional syndromes as FD and the irritable bowel syndrome comes to be accepted as a clinical reality,92 it has posed a dilemma for those who seek to develop precise clinical definitions for the individual functional disorders. For example, where does NERD end and FD begin?1 This is far more than an issue of semantics; the inclusion of patients with predominant heartburn in a dyspepsia study population which examines the response to an acid-suppressing agent will significantly bias the study in a positive direction; as a corollary, the exclusion of heartburn, as advocated by some, will lessen the impact of the same agents. The approach to definition will similarly have a significant impact on studies of the epidemiology, pathophysiology and natural history of the respective disorders. The need to delineate succinct patient categories notwithstanding, the clinical reality is that many NERD patients complain of heartburn and dyspepsia; attempts to separate patients on the basis of the relative ‘predominance’ of one or other symptom complex seems unrealistic, if not impossible. For now, studies of acid exposure appear to be the most useful parameter for segregating NERD into subgroups that predict clinical behaviour, natural history and therapeutic response (Figure 1). Among the NERD subgroups, those with an abnormal acid-exposure time on a 24-hour pH study may well harbour subtle features of oesophagitis and are those most likely to respond to acidsuppressive therapy and to have a good outcome following fundoplication. While data is scanty, it is also evident that those with both a normal acid exposure time and a negative symptom-reflux association (functional heartburn) are least likely to respond to standard anti-reflux therapies. I propose that these individuals are those who truly overlap with FD (Figure 2) and that their clinical characteristics indicate that they

Functional dyspepsia (FD) and non-erosive reflux disease (NERD): overlapping or discrete entities? 701

AET + (45%) n

n

n

n

n

AET – SI + (6%)

Respond to PPI’s Respond to surgery Hiatal hernia more common Positive symptomreflux correlation May harbour microscopic oesophagitis

n

n

AET – SI – (49%)

True prevalence uncertain; only a minority of AET – will be SI + (11%) Hypersensitive to acid and mechanical stimuli

n

n

n

n

n

n

Poor or no response to PPI Fare poorly with surgery Hiatal hernia absent Equivalent to “symptomatic heartburn” Overlap with FD Equivalent to a FGID

SI = Symptom Index/Symptom-Reflux correlation AET = Acid Exposure Time NERD = Non-Erosive Reflux Disease FD = Functional Dyspepsia FGID = Functional Gastrointestinal Disorder Figure 1. NERD subgroups.

belong more appropriately in the spectrum of functional gastrointestinal disorders (FGID’s) than in that of GORD. This deliberate separation should spare these patients from wasteful and protracted courses of potent acid suppression and, above all, prevent potentially disastrous exposure to surgical options. Does this imply that all patients with NERD require pH monitoring before therapy can be initiated? This is not only impractical but unnecessary. An alternative strategy is the therapeutic trial of high-dose proton pump inhibitor; the PPI test.93,94 This approach will define, in a few days, those who respond to acid-suppression and who are likely to continue to benefit from this therapy, in the long term. While alternative approaches, including agents that attempt NERD

FD

Heartburn

+

+

+

+/–

pH

+

–

+

–

+

–

+

–

PPI Response

ACIDPEPTIC DISORDER = GORD

FGID = FD/IBS

Figure 2. FD/NERD interactions, a unifying hypothesis.

702 E. M. M. Quigley

to restore normal gastro-oesophageal motor function and modulate sensation, may, in theory, be of value to those with normal esophageal acid exposure or who demonstrate significant dyspeptic symptoms, there is, at the present time, little or no objective data available to support any of these proposals. Studies which clearly delineate the several facets of NERD and compare pathophysiology, natural history and therapeutic response among its principal subgroups are required to resolve the true nature of NERD and the real implications of NERD/FD overlap. Clinical Practice Points † both GORD and dyspepsia are very common in the community † NERD and FD are the most common manifestations of GORD and dyspepsia, respectively † NERD is a heterogenous disorder which may be differentiated on the basis of acid exposure on a 24 hour pH study † that NERD subgroup who do not exhibit any abnormality on pH testing are those who do not respond to acid suppression and will fare poorly if subjected to surgery † this latter subgroup overlap extensively with FD and other FGID’s; we propose therefore that this subgroup truly belongs in the spectrum of FGID and not GORD

Agenda for future research † community surveys documenting overlap between NERD and FGID’s † clinical studies to define relationships between the subgroups of NERD, as defined by pH studies and QOL, therapeutic response and prognosis † clinical studies examining mechanisms of symptom production in AET-negative NERD, e.g. sensation testing, perception studies

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