Q } MedW97; 90:75-78
Commentary
QJM
Gastro-oesophageal reflux disease—spectrum or continuum?
E.M.M. QUIGLEY
From the Section of Gastroenterology and Hepatology, University of Nebraska Medical Center,
Omaha, USA
Introduction
Several factors have led to a tremendous recent
increase in interest in the field of gastro-oesophageal
reflux disease (GORD). These include significant
advances in our understanding of the pathophysiology of GORD, 1 " 3 an appreciation of both the striking
prevalence of this disorder and of the ever-increasing
breadth of the spectrum of its presentations,4"7 the
development of new diagnostic tools, and, finally,
the advent of a number of new medical and surgical
approaches to therapy.8"13 Fundamental to any discussion of GORD and to real progress in this area
must be, firstly, a reasonable level of agreement, if
not consensus, on a definition of this disorder, and,
secondly, a clear understanding of its natural history—goals which have proven elusive and frustrating.
GORD definition
Gastro-oesophageal reflux disease is not a single
discreet entity and is, therefore, subject to a number
of definitions. In the past, GORD was variously
defined on the basis of symptoms, the presence of
an hiatal hernia, or evidence of target-organ damage
in the form of oesophagitis or its complications. We
now realize that some of these concepts are inaccurate, whereas others, such as oesophagitis, grossly
underestimate the frequency of reflux disease. More
recently, the focus in definition has shifted to the
concept of acid exposure and the widespread
application of 24-h pH studies has led to attempts
to define reflux disease on the basis of a pathological
degree of acid exposure; particularly relevant among
those without evidence of overt mucosal abnormality.14'15 Others have sought to define GORD, in this
latter population, on the basis of more subtle endoscopic changes or histological features. Most recently,
the spectrum of GORD has been extended to those
individuals whose total acid exposure appears normal
but whose symptoms appear to reflect an increased
sensitivity to refluxed acid. 16 " 18 Thus, another diagnostic approach attempts to assess acid sensitivity,
based upon the description of a correlation between
symptom occurrence and acid reflux during either
the more traditional Bernstein test or an ambulatory
24-h recording of intra-oesophageal pH. These extensions of the concept of GORD have obvious implications for our understanding of its prevalence, natural
history and epidemiology. In a disorder whose concept has already moved from one of gross targetorgan damage to subtle alterations in physiology,
where will the spectrum end? How reproducible are
these new definitions of reflux-related disease?
The answers to these crucial questions are not
available and must await consensus on the definition
of GORD, or the validation of a gold standard for
this disorder. As the spectrum of GORD expands,
we may also now ask whether this disease represents
a continuum. Can, for example, a 25-year-old with
symptomatic heartburn expect to progress through
oesophagitis to Barrett's in middle age? The answer
to this question is of vital importance in planning
therapy—should therapy for all be intense and continuous, as some have advocated,19'20 or should there
be, as one authority has suggested, earlier recourse
to surgery?13 Although scarcely supported by appropriate data, this concept of GORD as a progressive
Address correspondence to Dr EMM. Quigley, Section of Gastroenterology and Hepatology, University of Nebraska
Medical Center, 600 So. 42nd St, Omaha, Nebraska 68198-2000, USA
© Oxford University Press 1997
76
EMM. Quigley
disease has gained considerable credence; before it
becomes truly established, I believe that its basic
tenets deserve some examination. I would, indeed,
suggest that CORD may represent not so much a
continuum, but rather a spectrum which includes
some discrete sub-populations.
Spectrum of reflux-related disease—
GORD subpopulations
Perhaps the largest group of GORD patients are
those with typical (or atypical) symptoms of reflux
disease yet who exhibit no evidence of oesophagitis or its complications. I term these patients
symptomatic GORD (a term which should be
regarded as synonymous with endoscopy-negative
GORD). Available evidence suggests that, for the
most part, these patients do not progress to oesophagitis or other complications. 21 ' 22
This group includes a disproportionate representation of those with atypical presentations, such as
chest pain and cough. This poses a considerable
diagnostic problem, as although in recent studies
heartburn and acid regurgitation appear to be reasonably sensitive and highly specific symptoms
for GORD, many of the more clinically challenging
symptoms, such as chest pain, are far from sensitive
or specific.23
Up until now, and based on the assumption that
symptoms in patients in the symptomatic GORD
group reflect abnormal acid exposure, diagnostic
efforts have concentrated on their separation, in terms
of acid exposure, from normal subjects. This task must
rely on a universally-accepted definition of what
represents normal acid exposure—something which
remains elusive.15 The story may not end, however,
with agreement on an upper limit for acid exposure.
It is also increasingly recognized that within this group
of symptomatic GORD are patients who appear to be
unusually sensitive to acid, yet whose overall level of
acid exposure would be regarded as normal.16'18 Thus,
one group reported that 7% of their patients with
'typical' GORD symptoms exhibited a normal acid
exposure, yet demonstrated a significant symptomreflux correlation on 24-h pH study.16 The question
arises, therefore, as to whether symptoms in this
group, in general, occur not so much because of
abnormal exposure to refluxed gastric material, but,
rather, because of an alteration in sensitivity to, or
perception of, the refluxate. It is also apparent that
24-h pH studies are not predictive of disease progression or indicative of symptom severity in individual
subjects, again suggesting that there is more to this
disorder than just the extent of acid exposure. It is
also interesting that gastro-oesophageal reflux symptoms are common among patients with either irritable
bowel syndrome or non-ulcer dyspepsia, disorders in
which abnormal perception is increasingly recognized
as an important factor.
Perhaps the most easily-defined and readilyunderstood group of GORD patients are those who,
at presentation, exhibit oesophagitis and/or related
complications, such as stricture. In general, this
population tends to be older than those with symptomatic or endoscopy-negative GORD, raising the
possibility that this group, in fact, represents those
who have experienced either more severe or prolonged exposure to acid and pepsin. Though apparently obvious, this concept is by no means
established. Although scarcity of data renders meaningful conclusions on the natural history of GORD
impossible, there are certainly some studies that
suggest that, for the most part, patients with
endoscopy-negative GORD do not progress to
oesophagitis.21'22 Why do some patients develop
oesophagitis and others not? Do the former progress
because reflux of acid and pepsin is simply more
severe and prolonged, because of the presence of
an additional factor(s) in the refluxate or because of
an intrinsic deficiency or acquired failure of a
protective mechanism? Data on progression to complications within the population with oesophagitis is
also scanty, but again suggests that the likelihood of
stricture formation, for example, is relatively low.
The final subgroup are those with Barrett's oesophagus. These patients tend to be older at the
time of diagnosis; in comparison to those with
either symptomatic GORD or oesophagitis, Barrett's
patients tend to experience more reflux and exhibit
a greater degree of lower oesophageal sphincter
hypotension and oesophageal body peristaltic dysfunction. 24 These factors alone do not, however,
explain why some patients develop Barrett's and
others do not. Given the tremendous advances in
our understanding, at the level of molecular biology,
of the pathogenesis of other forms of metaplasia and
dysplasia in the gastrointestinal tract, I would not be
surprised if ongoing research revealed some basic
biological difference among Barrett's patients. This
biological factor, whether it be a genetic predisposition or a growth factor abnormality, may determine
why these patients respond to the same degree of
reflux with the development of metaplasia.
The GORD population may not, therefore, represent one homogenous group which inexorably progresses from one stage to the next, but may rather
represent a number of disparate populations who
share acid/pepsin exposure as a common factor, but
who respond to it in different ways (Table 1). Some
are unduly sensitive and develop symptoms, such as
chest pain, at levels of exposure which may in fact
be 'normal'. Others, perhaps because of some defect
in protective mechanisms, are prone to develop
mucosal injury, oesophagitis and related complica-
77
Gastro-oesophageal reflux disease
Table 1
The three main populations of GORD—differences in pathophysiology
Exposure
Resistance
Repair
Sensitivity
Symptomatic GORD
Oesophagitis
Barrett's
Normal/abnormal
Intact
Abnormal
Impaired
Normal
Normal
Abnormal
Impaired
Abnormal
Decreased
Increased
tions, while others still respond to reflux and refluxrelated damage by developing intestinal metaplasia,
perhaps on the basis of a genetically determined
defect in mucosal repair.
Mention was made above of the role of various
factors in defining the clinical and pathological
manifestations of CORD. Simply put, why do some
patients never develop oesophagitis and others
develop strictures and Barrett's? In general, loweroesophageal sphincter pressure tends to be lower in
those with more severe manifestations of the disease,
but whether this is a primary abnormality or a
secondary phenomenon is unclear. The same applies
to clearance mechanisms. It is well known that
peristaltic amplitude may be impaired in patients
with severe reflux disease; again, whether this is a
primary abnormality or secondary to oesophagitis
remains controversial. Is the timing of reflux relevant?
Some suggest that a major abnormality in those with
severe manifestations of GORD is the occurrence of
supine, or nocturnal, reflux. The role of transient
lower-oesophageal sphincter relaxations25 in determining the severity of expression of GORD has not
been extensively investigated, as yet. The nature of
the refluxate may also vary between subpopulations;
some, for example, have incriminated bile, alkali
and pancreatico-intestinal enzymes in the pathophysiology of Barrett's and its related adenocarcinoma. 26 'Host' factors also need to be addressed,
including obesity, work pattern, exercise and tobacco
and alcohol use.
One area that is finally attracting the attention it
deserves in the pathophysiology of GORD is the role
of mucosal protection, an area extensively investigated in the duodenum and stomach.27 While mucus
and bicarbonate do not appear to play a predominant
role in the oesophagus,28 epithelial factors seem to
be very important. The epithelial cell membrane
appears highly resistant to acid: intercellular connections and intracellular buffering mechanisms also
appear to play a role. The relative contributions of
these and other factors to the pathogenesis of oesophagitis remains to be defined.
Conclusions
As we move to evaluate new therapeutic options
and consider its ever-expanding spectrum, the time
has come to reassess our concept of GORD. This is
a diverse and multi-faceted disorder: within its everexpanding spectrum are included, I believe, a
number of discrete entities. The three major subpopulations, symptomatic GORD, oesophagitis and
Barrett's oesophagus, represent separate disorders
differentiated on the basis of host response to acid
exposure, as summarized in Table 1. Some patients
may move from one subpopulation to another, but
this is likely to be the exception rather than the rule.
Large prospective community-based studies alone
can delineate the natural history of this common and
important disorder. Considerable effort also needs to
be directed towards unraveling the factors that determine the varied expressions of GORD.
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