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2013 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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EDITORIAL
Abstract: Functional dyspepsia is a very common,
distressful, and costly condition. New data
indicate that heartburn and regurgitation occur
frequently in functional dyspepsia, even after
objective gastroesophageal reux disease has
been exhaustively excluded by appropriate testing.
Arbitrarily excluding heartburn in functional
dyspepsia studies appears misguided.
Am J Gastroenterol 2013; 108:775 777; doi: 10.1038/ajg.2013.102
Dyspepsia and refux symptoms are both remarkably common and
tend to travel together; in a telephone survey of over 21,000 adults
in the United States, the three most prevalent symptoms occur-
ring at least once a month were early satiety (reported by 23 % ),
heartburn (22 % ), and postprandial fullness (21 % ) ( 1 ). Heartburn
(a burning rising retosternal discomfort) and acid regurgitation
are considered classical gastroesophageal refux disease (GERD)
symptoms, which typically arise when abnormally increased tran-
sient lower esophageal sphincter relaxations allow gastric acid to
reach the distal esophagus. In GERD gastroduodenal dysfunction
is not thought to be of major relevance, although a subset also
have gastric emptying delay ( 2 ). Patients ofen do not know what
the word dyspepsia means and one might argue many physicians
do not either; dyspepsia is not uniformly defned in the literature
( 3,4 ). In the United Kingdom, dyspepsia refers to epigastric pain,
heartburn, or any other upper gastrointestinal (GI) symptom ( 4 )
which is not terribly useful. Some physicians still use really vague
terms such as gastritis (or worse gastropathy) to describe symp-
toms thought to arise from the gastroduodenal region ( 3,4 ).
Te current international Rome III consensus, based on expert
opinion, is that dyspepsia should be restricted to only one of the
four cardinal gastroduodenal symptoms (the dyspepsia complex ):
epigastric pain, epigastric burning, early satiety (inability to fn-
ish a normal-sized meal), and / or postprandial fullness; heartburn
is considered to be quite distinct and not part of dyspepsia ( 3 ),
even though most have a cluster of symptoms, not one or two
( 5 ). Early satiety and postprandial fullness can occur when the
proximal stomach fails to relax or the stomach is hypersensitive
to mechanical distension ( 6 ). Epigastric pain or burning might
arise from acid bathing the esophagus, stomach, or duodenum,
based on experimental data, but is also most ofen attributed
to gastroduodenal and not esophageal dysfunction ( 7 ). Practice
guidelines currently recommend diferent pathways if a patient
presents with predominant heartburn vs. those presenting with
one of the four cardinal dyspepsia symptoms; for example, empiric
Helicobacter pylori test and treat is only recommended in the
dyspepsia pathway ( 8 ).
If you read the Montreal classifcation of GERD ( 9 ) and the
Rome III classifcation of functional dyspepsia ( 3 ), you would
be forgiven for concluding that endoscopy-negative GERD and
functional dyspepsia are distinct disorders easy to pry apart in
research and practice. Among those presenting with upper GI
symptoms in primary and secondary care, it has been generally
assumed that the presence of frequent heartburn or acid regur-
gitation, especially if one of these is the predominant symptom,
indicates the patient almost certainly has GERD even if dyspepsia
coexists. Vakil and colleagues ( 10 ) in this issue of the American
Journal of Gastroenterology present data that cast doubt on the
assumption GERD and dyspepsia are distinguishable based on
heartburn. If we cannot use symptoms, how do we guide optimal
therapy in practice? In this Editorial, lets review what we do know,
what have we learned from the Vakil paper, and where to go from
here for both research and practice.
Emerging data support the view that heartburn and dyspepsia
are really part of one disease complex. For example, in epide-
miological studies, heartburn is recognized to occur commonly
in those reporting dyspepsia, in fact more so than expected by
chance despite heartburn and dyspepsia being such frequent
complaints ( 5,11 ). Limited pathophysiological data also support
a link, although why there is the co-occurrence of dyspepsia and
GERD symptoms is not well conceptualized. Gastric emptying is
delayed in a subset of patients with GERD (perhaps one-third),
but gastric emptying correlates very poorly with symptoms unless
Functional (Non-Ulcer) Dyspepsia and Gastroesophageal
Reux Disease: One Not Two Diseases ?
Nicholas J. Talley , MD, PhD
1


1
University of Newcastle , Callaghan , New South Wales , Australia . Correspondence: Nicholas J. Talley, MD, PhD , University of Newcastle , Callaghan ,
New South Wales 2308 , Australia . E-mail: nicholas.talley@newcastle.edu.au
Received 6 March 2013; accepted 7 March 2013
The American Journal of GASTROENTEROLOGY VOLUME 108
|
MAY 2013 www.amjgastro.com
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776 Talley
Most of the randomized trials in functional dyspepsia have tried
to exclude GERD and have relied on asking about heartburn to rule
out refux ( 3,4 ). However, this approach may actually have ensured
that an atypical functional dyspepsia population was recruited; the
Vakil data support the concept that heartburn is an integral part
of the dyspepsia complex. An example of this paradox (excluding
heartburn may reduce the observed therapeutic response in func-
tional dyspepsia) has potentially been demonstrated. Itopride is a
prokinetic agent via dopamine D2 antagonism and antiacetylcho-
linesterase activity. In a carefully conducted Phase II trial, itopride
was superior to placebo in patients with functional dyspepsia, but
heartburn was not an exclusion ( 15 ) . In a subsequent Phase III
program comprising two similar randomized placebo control-
led trials, following advice from the Food and Drug Administra-
tion, refux symptoms were more rigorously excluded, itopride
was overall no better than placebo ( 16 ). In a subgroup analysis,
heartburn was the best predictor of response to itopride in the
Phase III program. Now we can speculate because heartburn is a
common, even characteristic symptom of functional dyspepsia,
excluding these cases will dampen response rates a revelation for
future trial design. A recent meta-analysis has suggested itopride
is superior to placebo in functional dyspepsia when all the data
are pooled ( 17 ).
In functional dyspepsia treatment trials, identifying and poten-
tially stratifying by the subgroups EPS and PDS is now widely
accepted, but Vakil and colleagues ( 10 ) suggest in primary care
that such subgrouping is likely of limited value because the condi-
tions overlap; in their study 66 % had both PDS and EPS. While
in epidemiological studies it has been easier to separate EPS and
PDS and overlap has been less striking ( 5,18 ), other studies in ter-
tiary care have similarly identifed the overlap of PDS and EPS as
dominating the clinical setting ( 19 ). Does this mean all comers
very severely impaired ( 12 ). While gastric accommodation is well
accepted to be impaired in a subset with functional dyspepsia
(perhaps as high as 40 % ) ( 3,4,6 ), Tack and colleagues ( 13 ) have
also shown that among those with a diagnosis of functional dys-
pepsia assessed by 24-h esophageal pH testing, impaired gastric
accommodation was actually numerically more common in those
dyspeptics with an abnormal esophageal pH study (although the
diference was not signifcant). In GERD, impaired accommoda-
tion may in part account for associated dyspeptic complaints such
as early satiety. Other data indicate that acid suppression may
beneft not only refux symptoms but also dyspepsia in patients
with GERD, supporting a direct relationship between heartburn
and dyspepsia ( 14 ).
In the Vakil study ( 10 ), primary care patients with one or more
upper GI symptoms at least twice a week for a month or longer
were recruited from Canada and Europe. Patients completed a
physician assessment, validated questionnaire, esophagogastrodu-
odenoscopy, and 48-h esophageal pH testing. GERD was defned
objectively by either esophagitis, pathological acid refux, or a
positive symptom associated profle, while functional dyspepsia
cases were broadly defned as upper GI symptoms with no objec-
tive evidence of GERD or peptic ulcer; excluding peptic ulcer, 189
(58 % ) had GERD whereas 138 (42 % ) had functional dyspepsia.
It was striking that typical symptoms of functional dyspepsia
occurred in over 80 % with GERD, but on the other hand heart-
burn and acid regurgitation were common in dyspepsia regard-
less of underlying Rome III symptom grouping into postprandial
distress syndrome (early satiety or postprandial fullness PDS) or
epigastric pain syndrome (epigastric pain or epigastric burning
EPS; Figure 1 ). In other words, symptoms classically attributed to
refux disease do not seem to help determine who does and does
not have functional dyspepsia.
53.8%
69.2%
66.7%
66.7%
59.3%
52.3%
81.5%
72.8%
0%
50%
100%
Heartburn Regurgitation Heartburn Regurgitation
64.5%
45.2%
73.8%
73.8%
PDS EPS PDS+EDS
Functional dyspepsia
P=0.7 P=0.3
P=0.7
P=0.2
Positive GERD testing
Figure 1 . Prevalence of dyspepsia subgroups (by Rome III) in those with documented functional dyspepsia (normal esophageal pH) vs. gastroesophageal
reux disease (abnormal esophageal pH study etc). Data from Vakil et al. ( 10 ). EPS, epigastric pain syndrome; GERD, gastroesophageal reux disease;
PDS, postprandial distress syndrome.
2013 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
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777 Editorial
must be included in future functional dyspepsia trials? I think not.
Accumulating evidence suggests functional dyspepsia is a hetero-
geneous disorder, and while we need to better dissect this het-
erogeneity, subgrouping by symptoms is likely of assistance. For
example, a potential biomarker in functional dyspepsia (duodenal
esoinophilia) was only identifed in PDS, not EPS ( 20 ); if causal,
those with duodenal eosinophilia are likely to respond difer-
ently to those who develop functional dyspepsia via an alternative
mechanism. Montelukast in children has been shown to reduce
dyspepsia symptoms and possibly stabilize eosinophil degranu-
lation, but more robust trials are urgently needed ( 21 ). Targeted
drug therapy by symptom subgroup also appears promising.
Acotiamide is a selective anticholinesterase inhibitor that has
prokinetic properties. In a recent controlled trial that randomized
only patients with functional dyspepsia and PDS, 52 % on active
drug responded (vs. 35 % on placebo), for a number needed to
treat of six ( 22 ). While impressive overall, it is interesting to spec-
ulate why a subset of PDS respond and other with similar symp-
toms did not are there at least two diferent types of PDS?
Functional dyspepsia is a very common, distressful, and costly
condition. Te new data indicate that heartburn and regurgitation
occur much more ofen than has been expected in functional dys-
pepsia, even afer objective GERD has been exhaustively excluded
by appropriate testing; arbitrarily excluding heartburn in func-
tional dyspepsia studies appears misguided, and guidelines may
need to be rewritten. One could speculate functional dyspepsia
may ofen now be misdiagnosed as GERD in clinical practice,
although this needs to be confrmed. Many patients with func-
tional dyspepsia have both PDS and EPS, but despite the overlap
there is evidence a symptom-based approach may help identify
biomarkers and partially guide therapy. Targeting subgroups of
functional dyspepsia based on a combination of pathophysiologi-
cal markers and specifc symptoms (e.g., duodenal eosinophilia
and early satiety?) may lead to new therapeutic breakthroughs .
C ONFLICT OF INTEREST
Te author declares no confict of interest.
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