NON-EROSIVE REFLUX DISEASE (NERD) AND FUNCTIONAL HEARTBURN

NON-EROSIVE REFLUX DISEASE (N E R D) AND FUNCTIONAL HEARTBURN

E. M. M. Quigley

Head of the Medical School, National University of Ireland, Cork, Ireland

Introduction

Most individuals with symptoms compatible with gas- troesophageal reflux disease (GERD) who undergo endoscopy will not show evidence of erosive esopha- gitis. Indeed, it is now clear that non-erosive or nega- tive-endoscopy reflux disease (NERD) [also referred to as endoscopy-negative reflux disease (ENRD) ], may account for up to 70% of patients with GERD in the community [1]–[3]. This contrasts with the spectrum of patients seen in a gastroenterological practice or ter- tiary referral center, where esophagitis and complicated GERD may predominate. However, until recently, most studies of diagnostic or therapeutic interventions in GERD were performed in the latter setting and may well, therefore, not be representative of the true spectrum of GERD . It is appropriate, therefore, to re- view our understanding of the clinical features, natural history, pathophysiology, evaluation and management of GERD , recognizing that the majority of patients have NERD and not erosive reflux disease (ERD) or one of its complications.

Definitions 1. NERD

Patients with NERD do not, by definition, have esophagitis and appear to be at low risk to develop esophagitis; NERD is best defined, therefore, on the basis of symptoms and/or their impact on an indi- vidual’s health-related quality of life (QOL) [4]. In- deed, it is apparent that NERD patients can, and do, suffer from symptoms as severe as those with ERD , and the impact on quality of life can be at least as disabling in NERD as in other manifestations of GERD [5], [6]. It is appropriate, therefore, that re- cent definitions of GERD incorporate the issue of

quality of life [4]. In defining NERD , one must be cognizant of prior therapy; an esophagus rendered free of esophagitis by acid-suppressive therapy does not constitute NERD . Attempts to define GERD on the basis of histological findings, in those in whom the mucosa is endoscopically normal, have also prov- en disappointing [7], [8].

Fass and colleagues have suggested that NERD may be further defined and sub-classified based on the results of 24-hour pH recordings in to three dis- tinct groups [9] (Fig. 1):

(i) Those with an abnormal acid exposure time (AET) ; these individuals appear to behave, in terms of therapeutic response, in a manner ana- logous to those with obvious esophagitis,

Fig. 1. GERD subgroups

between symptoms and acid exposure; needless to say, there is no macroscopic or microscopic evidence of acid-related mucosal injury. The precise prevalence of this disorder is unknown; estimates suggest that approx- imately 40% of NERD patients (or 20% of all GERD ) will fall into this category [3], [17]–[19] and its patho- physiology remains virtually unexplored [20]. Clinical impressions suggest that there is considerable overlap with other functional disorders such as irritable bowel syndrome and non-cardiac chest pain; one can assume, therefore, that such phenomena as visceral hypersensi- tivity and abnormal cerebral perception of visceral events may be involved. Anecdotal evidence, derived largely from referral centres, suggests a significant role for psychological factors; given the context of this observa- tion and of prior experience with the perils of extrapola- ting from a referral sample to the community in other functional disorders, one needs to exert extreme caution in the interpretation of this association, however.

Pathophysiology

While gender and age are by no means absolute dis- criminators for any group of GERD , it is noteworthy that, in contrast to GERD , in general, females do pre- dominate in NERD , a group who, on the whole, tend to be younger, by a factor of about a decade, than their erosive GERD counterparts. Existing data on the pathophysiology of NERD suggest that while, as in ERD , acid and pepsin play a central role in the induc- tion of symptoms, abnormal esophageal acid exposure cannot be the sole mechanism. Thus, on ambulatory esophageal pH testing, the acid exposure time (AET) , expressed as the total percentage of time that the pH is less than 4, is abnormal in only one-half to two- thirds of NERD patients [9], [21]. In the remainder, GERD may be defined on the basis of a positive cor- relation between symptom onset and reflux events [22]. As a result, it has been suggested that these indi- viduals are hypersensitive to physiological degrees of esophageal acid exposure. Experimental evidence to support this concept comes from studies which have demonstrated that these patients are hypersensitive to intra-esophageal balloon inflation, in comparison to both control subjects and to GERD patients with ab- normal AET [22], [23]. Fass and colleagues failed, however, to demonstrate an effect of acid exposure on (ii) Those who demonstrate a normal AET but in

whom symptoms and reflux events are signifi- cantly correlated (as estimated by some form of symptom index or other measure of symptom- reflux event association); these individuals have been referred to as “the sensitive esophagus”

[10],

(iii) Those with typical reflux symptoms (i.e., heartburn and acid regurgitation), yet in whom all parameters of the pH study are normal.

These individuals appear highly resistant to acid-suppressive therapy [10] and are more likely to demonstrate psychopathology [11].

The definition of functional heartburn is especially problematic and confusing. For example, the second iteration of the “Rome” criteria [12] and other ex- perts [13]–[15] incorporate groups (ii) and (iii), above, in the definition of functional heartburn.

Given that classification should advise diagnostic and therapeutic decisions and predict pathophysiology, most clinicians would reserve this term for group (iii) alone. This is also the opinion of this author; it is, to my mind, counterproductive and well as counterintu- itive to include two quite distinct groups of patients (i.e., those who do and do not demonstrate an asso- ciation with acid exposure and a response to acid suppression) in the same category.

This reliance on pH data could be construed to imply that this test plays a pivotal and essential role in the evaluation of NERD . If one accepts that the true NERD patient (as distinct from the individual with therapeutically-resolved esophagitis) is at low risk for progression to such worrisome complica- tions as Barrett’s esophagus, then a therapeutic trial (also referred to as the PPI test) emerges as a valid diagnostic alternative [16]. This approach has the additional benefit of rapidly identifying those who are likely to benefit from long-term PPI therapy.

2. Functional heartburn

Among the various manifestations of GERD described

so far in this review, functional heartburn may represent

the greatest challenge to the clinician. Affected patients

present with typical reflux symptoms, yet, as described

above, all diagnostic modalities fail to reveal either

evidence of pathological acid reflux or an association

mechano-sensitivity, in their study; they did, however, describe an accentuation of the chemo-sensitive re- sponse to acid following prolonged acid exposure [24].

Visceral hypersensitivity has, of course, been invoked as an important factor in the etiology of such functional gastrointestinal disorders as non-cardiac chest pain, functional dyspepsia and the irritable bowel syndrome. It should come as no surprise, therefore, that there is accumulating evidence to indicate an overlap between NERD and functional dyspepsia [25], [26]; in our own experience, up to 50% of NERD patients have dysmotility/dyspeptic symptoms [27].

Is NERD truly non-erosive? Ultrastructural stud- ies on human tissues, as well as experimental animal models, have demonstrated dilatation of the inter- cellular spaces in the esophageal epithelium in esophagi that look macroscopically normal [28]–

[30]. Such changes could increase permeability and facilitate access for acid to submucosal neurons, thereby, inducing either spasm and/or visceral hypersensitivity [9]. Given the very low rate of pro- gression, among NERD patients, to more obvious mucosal disease [31]–[39], it seems most unlikely that these subtle changes are the harbingers of esophagitis to come. Recent studies employing mag- nification and other techniques have revealed subtle abnormalities at the gastro-esophageal junction in NERD [40], [41]; how these findings relate to symptoms and to possible disease progression re- main to be defined.

What is the etiology of functional heartburn?

Given that acid exposure is, by definition, normal in affected patients and episodes of acid exposure do not predict symptoms, one must look elsewhere to explain the precipitation of heartburn in this popu- lation. Pending definitive study and based on our experience with other functional gastrointestinal disorders, it seems reasonable to propose likely roles for visceral hypersensitivity, abnormal central per- ception and psychopathology, among others [20]. It is also clear that stimuli other than acid can evoke typical heartburn [24] and that the pathophysiology of heartburn even in “classical” GERD is complex [42], [43]. Utilising miniaturised intraluminal ultra- sound probes, Mittal and colleagues have, for exam- ple, revealed acid-induced episodes of shortening of the longitudinal muscle layer in relation to the oc- currence of heartburn, thereby, revealing another

mechanism whereby acid may induce symptoms [42]–[44]. Whether this and other methodologies, such as intra-luminal impedance measurements [45]–[47], to detect reflux of gas and non-acid liquid components of the refluxate, and brain mapping studies [48], to identify the cortical representation of esophageal symptoms, will reveal as yet unrecog- nised associations between luminal acid, bile or other agents in the refluxate and symptoms in functional heartburn, remains to be defined. Even in functional heartburn, where acid exposure is normal and tem- poral associations between acid reflux and symptoms are not readily identified, acid cannot be discounted.

Prior, or even remote, episodes of physiological reflux may sensitise the esophagus, in predisposed individuals, to the subsequent development of symp- toms in relation to non-acid stimuli [43], [49].

Hyperensitivity to acid may, indeed, reflect sensitiza- tion of afferent neurons leading from the esophagus to the central nervous system [20].

Available evidence does indicate that the more one strays into the realm of those with normal pH studies in a heartburn population, the lower the re- sponse to acid suppression and the greater the over- lap with other functional disorders. To date, however, most studies of NERD pathophysiology have failed to differentiate between the various subgroups of NERD and, in particular, to separate out those with functional heartburn. Those that have indicate, as one would predict, that NERD patients with abnor- mal acid exposure and acid hypersensitivity resemble patients with erosive and complicated esophagitis whereas parameters of esophageal physiology are more closely akin to normal subjects among those with functional heartburn [50]. Fass and Tougas suggest that symptom induction in the functional heartburn patient represents a complex interaction between the intraluminal stimulus, esophageal recep- tors, visceral afferent neurons and central perception [20]. In keeping with other functional disorders, it is to be expected that a hypervigilant brain, sensitized, perhaps, by environmental or intrinsic stressors may play a significant role.

For all of these reasons, this author proposes that

future definitions of this subpopulation will remove

functional heartburn patients from the spectrum of

GERD and place them where they belong, among

the functional gastrointestinal disorders.

NERD and dyspepsia

As overlap between these functional syndromes comes to be accepted as a clinical reality, it has posed a dilemma for those who seek to develop precise clinical definitions for the individual functional dis- orders. For example, where does NERD end and functional dyspepsia begin? [51] 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 [52], [53]; as a corollary, the ex- clusion of heartburn, as advocated by some [54], 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 notwithstand- ing, 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. Other data sup- ports the overlap between the disorders.

Firstly, the intimacy of physiological relation- ships between the lower esophagus and the upper stomach continues to be revealed. Thus, fundic dis- tension is a primary mechanism of induction of transient lower esophageal relaxations ( TLESR ’s) [55]; which are, in turn, responsible for most epi- sodes of reflux in both health and in GERD [26].

Secondly, similar disturbances in upper gut motility, including gastric emptying delay, have been de- scribed in NERD and functional dyspepsia [26]. In functional dyspepsia, impaired fundic accommoda- tion appears to be a prominent feature [56]. Very recent data suggest that dysfunction of the upper stomach may occur in NERD also [57], [58]. Just as the overlap with functional dyspepsia, and the po- tential role of motility and or sensory dysfunction in symptom generation, have been implicated to ex- plain the relatively inferior response to proton pump inhibitors in NERD , these same factors have encour- aged investigation of a potential role for prokinetic agents. To date there have been few studies of pro- kinetic agents in NERD ; those that have been per- formed have not proven encouraging [27], [59], [60].

Assessment

Can one predict NERD on the basis of clinical evalua- tion? While the NERD patient is, on average, younger and more likely to be female that the individual with complicated GERD , these demographic features are not sufficiently discriminating to be of diagnostic val- ue. In terms of typical GERD symptoms, neither se- verity nor duration can discriminate between NERD and GERD , or predict complications or manometric or pH study results. Some atypical or extraesophageal symptoms, in contrast, tend to be associated with NERD and may in of themselves predicate a different therapeutic strategy. It has been suggested, for exam- ple, that both laryngitis and asthma related to GERD require more intensive and more prolonged acid- suppressive therapy in order to optimise symptomatic response. It is also abundantly clear that this area con- tinues to suffer from a striking paucity of data derived from randomised controlled clinical trials.

Many approaches may be taken to the evaluation of the individual presenting, for the first time, with symptoms indicative or suggestive of GERD . Deci- sions regarding the extent of assessment are based on individual patient factors and on some generic issues.

With regard to the former, patient age and nature of

symptomatology are fundamental; few would dispute

the appropriateness of endoscopy in a 63-year old

patient with heartburn and dysphagia referred to the

lower esophagus. More controversial are the generic

issues and one, in particular, Barrett’s esophagus. One’s

assessment of the role of Barrett’s in the pathogenesis

of esophageal adenocarcinoma and one’s attitude to

the efficacy and appropriateness of screening and sur-

veillance policies for this manifestation of GERD will

determine enthusiasm for such approaches to GERD

as “once in a life-time endoscopy for every GERD

patient” or “endoscopy for all over 50”. In the absence

of conclusive data, approaches are largely empiric and

extend from one of recommending endoscopy in all

GERD patients to a position which, unimpressed by

the efficacy of either screening or surveillance, would

not factor Barrett’s into the equation when making

decisions on evaluation. Endoscopy may have other

roles in assessment. These include the obvious value of

defining GERD , on the basis of endoscopic findings,

in a patient with atypical or non-responsive symptoms

and also the less well-defined role of endoscopic fea-

tures in predicting long-term prognosis and therapeu- tic response. If, as some evidence suggests, GERD phenotypes remain stable, over time, this has funda- mental implications from a management perspective.

In choosing a therapeutic strategy for a NERD patient, for example, one can do so confident that pro- gression to esophagitis or Barrett’s esophagus is so un- likely that the effect of a particular treatment modality on natural history is not an issue. Several studies from Lagergren and colleagues, in Sweden, have raised a note of caution in this regard. Their suggestion that the risk for adenocarcinoma of the esophagus, in the patient with GERD , relates to heartburn frequency, severity and duration and not to such mucosal pathol- ogies as Barrett’s epithelium [61], certainly requires confirmation but cannot be ignored.

Management

Of interest, several studies as well as recent reviews and meta-analyses, while confirming a significant response, in terms of symptom relief, to proton pump inhibitors in NERD , have demonstrated, with some consistency, that these agents are somewhat less effective in NERD [3], [9], [59], [62]–[68] than in ERD [69]. Several factors might explain this somewhat unexpected finding and include the rela- tively greater importance of abnormal acid exposure in ERD and the significant overlap with functional dyspepsia and other functional disorders [64], in NERD ; a disorder where acid suppressing agents have a far smaller impact than in GERD [51], [52].

This is not to say that NERD patients with dyspep- sia do not respond to proton pump inhibitors; in- deed, functional dyspepsia patients with heartburn are perhaps those most likely to respond to acid suppression [51]–[53]. At the present time there is relatively little information on the use of non-acid suppressing approaches in NERD [62]. In terms of other forms of acid suppression, studies of histamine H2-receptor antagonists in NERD [62], [65], [70]

suggested a response rate similar to, and as disap- pointing as, that seen in ERD [71], [72]. For the moment, at least, potent acid suppressing agents, such as proton pump inhibitors, remain the first-line option for these patients. The response is not opti- mal and other approaches to restore normal motor

function and modulate sensation may be of value to those with normal esophageal acid exposure or who demonstrate significant dyspeptic symptoms.

While the natural history of NERD remains poorly documented, available evidence suggests a benign course. Symptom control and restoration of quality of life become the primary therapeutic goals, therefore [73]. These concepts, together with the ex- pense of sustained proton pump inhibitor therapy, have prompted an evaluation of on-demand therapy for NERD patients [74]–[77]. This approach proved effective using omeprazole 20 mg per day; only 50%

of patients required the proton pump inhibitor, in addition to antacids, to maintain quality of life. On- demand therapy may represent a more cost effective approach to management for this large group of GERD patients. The adoption of this strategy necessitates an acceptance of the benign nature of NERD ; it must be stated that available data, though consistent in this regard [31]–[39], are far from ade- quate to permit a definitive statement on the natural history of this disorder. The recent suggestion that adenocarcinoma risk relates to heartburn frequency, severity and duration and not mucosal pathology [61], must also be taken into account.

The introduction of the laparoscopic approach

has revolutionized the surgical approach to GERD

and has led to a virtual epidemic of fundoplication

procedures. Not surprisingly, many patients with

NERD are being considered for, and subjected to, lap-

aroscopic fundoplication. The precise proportion of

NERD patients in surgical series is often difficult to

discern as the effects of prior acid-suppressive medi-

cation is usually not accounted for in describing pre-

operative endoscopic findings. Several recent pieces

of evidence indicate that the clinician needs to exert

cautious and careful judgement in considering the

surgical option in 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 symp-

tomatic response to acid suppression [78], [79]; fea-

tures not common to all NERD patients. Secondly,

it is evident that the NERD patient with prominent

dyspeptic features may fare especially poorly and be-

come crippled by gas-bloat and other symptoms

post-fundoplication. There is, indeed, a potential

pathophysiological explanation for these unfortunate

Conclusion

NERD is a real entity and its importance in the spectrum of GERD must be appreciated. Functional heartburn needs to be further differentiated as that subgroup of patients in which there appears to be no relationship between symptoms, albeit “typical” of GERD , and acid exposure. Several aspects of NERD need to be appreciated including the overlap with functional dyspepsia and potential differences in response to such therapeutic interventions as acid suppressive therapy and fundoplication. While de- finitive studies on this issue are yet to be completed, it remains quite possible that our failure to separate functional heartburn from NERD , in general, has contributed in large measure to diagnostic difficul- ties and therapeutic disappointment in GERD . This author contends that functional heartburn should be removed from the spectrum of GERD and relocated to the functional gastrointestinal disorders; only then will effective approaches to the assessment and therapy of this challenging disorder emerge.

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