Clinical Gastroenterology and Hepatology 2018;16:467–479
NARRATIVE REVIEWS
Definition, Pathogenesis, and Management of
That Cursed Dyspepsia
Pramoda Koduru, Malcolm Irani, and Eamonn M. M. Quigley
Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston
Methodist Hospital and Weill Cornell Medical College, Houston, Texas
Dyspepsia is an umbrella term used to encompass a
number of symptoms thought to originate from the upper
gastrointestinal tract. These symptoms are relatively
nonspecific; not surprisingly, therefore, a myriad of con-
ditions may present with any one or a combination of these
symptoms. Therein lays the clinician’s first challenge:
detecting the minority who may have a potentially life-
threatening disorder, such as gastric cancer, from a popu-
lation whose symptoms are, for the most part, considered
functional in origin. The second challenge lies in the defi-
nition and management of those individuals with func-
tional dyspepsia (FD); the major focus of this review. The
Rome process has addressed the issue of FD definition and
a look back at the evolution of Rome criteria for this dis-
order illustrates the complexities that have so frustrated
us. There has been no shortage of hypotheses to explain
symptom pathogenesis in FD; initially focused on gastric
sensorimotor dysfunction, these have now strayed well
into the duodenum and have come to entertain such fac-
tors as immune responses and the microbiome. FD has
proven to be an equally challenging area for therapeutics;
while the staple approaches of acid suppression and
eradication of Helicobacter pylori have some limited effi-
cacy in select populations, strategies to ameliorate symp-
toms in the majority of sufferers based on presumed
pathophysiology have largely foundered. Lacking a vali-
dated biomarker(s) FD continues to be an elusive target
and is likely to remain so until we can better define the
various phenotypes that it must surely contain.
Keywords: Dyspepsia; Functional Dyspepsia; GERD; IBS;
Helicobacter pylori; Proton Pump Inhibitor; Prokinetic;
Gastroparesis.
yspepsia (literally bad digestion), or as it is more
D commonly referred to in general parlance, indi-
gestion, has been around for millennia. References to
indigestion/dyspepsia can be traced back to the writings
of Hippocrates and Galen, if not earlier,1 and have
featured in the works of great writers ever since. In
Cymbeline, Shakespeare informs us that “if you are sick
at sea or stomach-qualm’d at land, a dram of this will
drive away distemper,” and in Coriolanus we learn that
“no; but it is the bosom which first feels the load of
repletion and indigestion” (perhaps a reference to
impaired fundic compliance).2 James Joyce, a giant of
20th century literature and an individual (based on his
Fasiha Kanwal, Section Editor
own somewhat peripatetic engagement with the disci-
pline) fascinated by medicine brings us right up to date
in Ulysses: “Tom Rochford spilt powder from a twisted
paper into the water set before him. —That cursed
dyspepsia, he said before drinking. —Breadsoda is very
good, Davy”.3 The early medical literature was similarly
preoccupied by the topic and various bodily dysfunction
or humors identified as culprits. By the mid-19th century
roles for gastric acid, motility, and maldigestion were dis-
cussed; overlap with heartburn mentioned; and a role for
the duodenum proposed.4
Dyspepsia is clearly a symptom that the general
public experiences and one that impacts on their well-
being; the dilemma lies in understanding and quanti-
fying what patients are trying to tell clinicians. What do
they mean when they complain of indigestion and what
do clinicians seek to convey when using the term
dyspepsia? How can this apparently common problem be
translated into a terminology that can be objectively
measured?
More than 25 years ago Crean et al5 in Glasgow,
Scotland attempted to grapple with this task and as a
result of their labors produced what is still one of the
most comprehensive descriptions of dyspepsia in an
urban environment. They defined dyspepsia as an
“episodic recurrent or persistent abdominal pain or
discomfort, or any other symptoms referable to the up-
per alimentary tract, excluding bleeding or jaundice, of
duration 4 weeks or longer” and acknowledged that
multiple symptoms could be included: “abdominal pain/
discomfort, heartburn or other manifestations of gastro-
oesophageal reflux, anorexia, nausea and vomiting,
flatulence or air eructation (belching, burping or
aerophagy), early satiety or undue repletion after meals,
abdominal distension or ‘bloating’ and symptoms
attributed by the patient to ‘wind’”5; thereby opening the
Abbreviations used in this paper: EPS, epigastric pain syndrome; FD,
functional dyspepsia; GERD, gastroesophageal reflux disease; IBS,
irritable bowel syndrome; PDS, post-prandial distress syndrome; PI,
postinfectious.
Most current article
© 2018 by the AGA Institute
1542-3565/$36.00
https://doi.org/10.1016/j.cgh.2017.09.002
468 Koduru et al
Pandora’s box that has bedeviled ever since. What
symptoms should be included? Does one allow overlap
with gastroesophageal reflux disease (GERD) and/or
irritable bowel syndrome (IBS)? Crean’s study also pro-
vides a clear picture of the disease spectrum encom-
passed within this definition of dyspepsia in an era when
Helicobacter pylori was in its infancy and such concepts
as nonerosive reflux disease had yet to emerge. Of the
1433 outpatients that they studied, 26% had a duodenal
ulcer, 9% had GERD, 4% gallstones, and 3% gastric
cancer5; in 37% dyspeptic symptoms were considered as
being functional in origin and assigned a diagnosis of
functional dyspepsia (FD) in 22% and IBS in 15%.
Although rates of duodenal ulcer disease have fallen
dramatically and those of GERD have risen in the United
States and Western Europe since then,6–9 it must be
remembered that duodenal and gastric ulcers remain
common causes of dyspepsia elsewhere.10–14 These
geographic variations in the relative prevalence rates of
organic and FD are undoubtedly related in large part to
varying rates of H pylori infection15 and also underscore
a fundamental issue in the development of any diag-
nostic or therapeutic strategy in dyspepsia: the preva-
lence of organic disease. If the latter is high, diagnostic
modalities, such as endoscopy, provide a high yield and
therapeutic interventions, such as acid suppression
and eradication of H pylori, have their greatest impact.
National, regional, and ethnic variations in prevalence of
gastric and esophageal cancer and complicated GERD
also influence diagnostic approaches, given that even in
gastric cancer alarm symptoms and signs are of modest
predictive value.16 Indeed, the ability to predict the
presence of most organic causes of dyspepsia (with the
possible exception of GERD) based on presenting
symptoms leaves a lot to be desired.5
It is critical to clearly differentiate between unin-
vestigated dyspepsia and FD in any consideration of the
management of these symptoms and to further consider
the impact of prior therapy on endoscopic findings.
Although the uninvestigated sufferer may harbor, given
the nonspecificity of his or her symptoms, any one of a
host of conditions, all organic causes have, by definition
been excluded in the individual with FD. Unsatisfactory
as it is, FD is a diagnosis of exclusion with the extent of
the search for an organic cause being guided and
tempered by the sufferer’s presentation, locale, prior
history, and all other relevant personal and environ-
mental factors. The shibboleths that clinicians cling to
are not as trusty as they seem; stress, so traditionally
linked to functional disorders, is a precipitant of
dyspepsia in general.5,17,18 Furthermore, language and
cultural factors may inhibit a real understanding of the
nature of the very symptoms that the sufferer seeks to
convey19 and unconscious physician bias may unwit-
tingly steer the diagnosis in a certain direction. Indeed,
prospective surveys have confirmed what many sus-
pected: FD is a label less commonly used in the United
States, where patients with FD-type symptoms are
Clinical Gastroenterology and Hepatology Vol. 16, No. 4
designated as GERD, perhaps reflecting a greater level of
comfort and optimism in treating the latter rather than
the former.20 It is also evident that dyspepsia is among
the most common symptom presentations in the rest
of the world as evidenced, for example, by data from
Latin America.21
Functional Dyspepsia: Toward a
Uniform Definition, a Visit to Rome
Although Rome criteria for IBS have remained
reasonably similar over the more than 30 years of the
process, those for FD have undergone very significant
changes.22 This reflects the aforementioned and
continuing struggle with the very definition of FD.
According to Crean et al5: “Although operational guidelines
have been proposed for the diagnosis ...of .. functional
dyspepsia, they fall short of explicit definition so that there
are no critical rules or rigorous paradigms against which
symptomatic diagnosis can be tested”; to put it simply,
there is no gold standard for the definition of FD.
The manner in which the definition of FD has evolved
within the Rome process, from one that included any
symptom referable to the upper gastrointestinal tract to
a more specific symptom cluster in the latest iterations
Rome III and IV, is testament to the confusion and con-
troversy that surrounds this entity.
Rome III represented a major departure from prior
definitions in 2 important respects.23 First, it subdivided
FD into 2 distinct syndromes: post-prandial distress
syndrome (PDS), characterized by meal-induced
dyspeptic symptoms and defined as bothersome post-
prandial fullness and early satiety for 3 or more days
per week; and epigastric pain syndrome (EPS), where
symptoms occurred in between meals. EPS was defined
as epigastric pain and/or burning for 1 or more days per
week. This subdivision was based on factor analysis
performed on symptom data derived from more than
2000 adults from the general population in Belgium that
identified meal-associated symptoms and predominant
pain as separate and distinct, a finding that was subse-
quently confirmed by other epidemiologic studies.24,25 It
also represented a significant departure from prior sub-
classifications that divided FD into “reflux-like,” “ulcer-
like,” “dysmotility-like,” or unspecified dyspepsia.26 The
relative contributions of PDS and EPS to FD have varied
in different studies. In a Canadian study of 850 adults
41% had the PDS subtype and 41% were classified as
an overlap of EPS and PDS27; in contrast, a study on 490
subjects with FD in Taiwan reported that 72% had PDS
subtype and 34% had an overlap of EPS and PDS.28 The
higher prevalence of PDS in Taiwan was thought to be
secondary to a higher prevalence of H pylori infection,
and particularly of the CagA-positive strain.28
Second, Rome III excluded from FD those who had
prominent heartburn or satisfied criteria for IBS.23 This
was to have major implications given the frequency of
April 2018
overlap among FD, IBS, and GERD and the much greater
response to acid suppression among those with “reflux-
like” dyspepsia; their removal not only flew in the face of
clinical experience but impacted greatly on clinical trial
outcomes. In terms of overall performance, and despite
these fundamental changes, Rome III criteria identified
patients with FD with a sensitivity of 60.7% and speci-
ficity of 68.7%; results that were not significantly
different from previous criteria.27
The latest iteration of the Rome process, Rome IV,
published in 2016, represents a significant departure from
prior versions with a much broader approach to the
definition and potential pathophysiology of functional
gastrointestinal disorders29 and now recognizes the
possible contribution of such phenomena as low-grade
inflammation, changes in the gut microbiota, and altered
brain processing to symptom pathogenesis.30,31 The clin-
ical definitions have also seen major changes.22 In relation
to FD, the absolutist approach of Rome III has been
dropped and Rome IV, instead, emphasizes that FD should
no longer be considered as a single disease entity but
rather as a spectrum where there is significant overlap
with GERD and IBS.32 Indeed, it was also recognized that
patients in this overlap experienced a higher intensity and
frequency of symptoms with greater impact on daily
life.33–37 In Rome IV, the syndrome of functional nausea
and vomiting is now identified as a distinct entity and
differentiated from FD32; the implications of this change to
diagnostic evaluation and management of nonorganic
dyspepsia are yet to be realized. The subclassification of
FD into PDS and EPS is preserved on the basis of some
(although by no means conclusive) evidence from epide-
miologic and pathophysiologic studies supporting their
separation28,38–41 and while acknowledging some degree
of overlap, especially, in referral populations.42 The defi-
nition of PDS is slightly altered to include epigastric pain
or burning that worsens with meals along with post-
prandial fullness and satiety. This alteration was based
on a study that patients should be classified primarily on
the post-prandial exacerbation of symptoms rather than
on their presence per se.43
Other changes introduced in Rome IV sought to pre-
cisely define minimum thresholds for frequency and
severity of symptoms primarily. Symptoms should be
severe enough to be bothersome (ie, distract from usual
activities) and should occur more frequently than the
normal population; at least 3 days per week for PDS and
1 day per week for EPS.44 Only time will tell if these new
Rome IV criteria are more effective in providing a
coherent and clinically relevant definition of FD.
Epidemiology of Functional Dyspepsia:
Where East and West Do Not Meet
The prevalence of FD has ranged between 10% and
30% among various studies, with a pooled global com-
munity prevalence of 21%.14,15 Here again the issue of
Dyspepsia - A Review 469
definition raises its ugly head: prevalence ranged from
7.6% when FD was defined based on ROME III criteria to
29% when a broad definition of upper abdominal or
epigastric pain or discomfort was used.15 Prevalence was
higher in women, and among smokers, nonsteroidal anti-
inflammatory drug users, and H pylori–positive
individuals.14,15
Geography is an important variable; although
dyspepsia is a global problem, there are significant dif-
ferences in prevalence, definition, epidemiology, and
clinical patterns between East and West, which can affect
the approach to the management of FD. FD is consis-
tently more common in Western than Eastern pop-
ulations,14 “ulcer-like” and “reflux-like” subgroups were
more prominent in Western populations,45 and
dysmotility-like-dyspepsia dominated in the East.14 In
Western populations, FD was associated with lower
socioeconomic class; in Eastern studies, it was more
frequent among those of higher socioeconomic sta-
tus.14,15 In Western populations, H pylori eradication has
resulted in a 10% therapeutic gain over placebo46; this
rate jumps to 15%–20% in studies of the same strategy
conducted in the East.47,48 Several factors, including
background prevalence of H pylori, diet, and lifestyle
characteristics, may contribute to these differences.
The economic impact of FD is significant but also
differs between East and West. The total direct and in-
direct costs attributable to FD in the United States were
estimated at $18.4 billion or $80,000 per 1000 US pop-
ulation.49 Two population-based studies in Malaysia
estimated the annual cost for uninvestigated dyspepsia
to be $14,816.00 and $59,282.20 per 1000 population in
a rural and urban setting, respectively, or an estimated
$1.02 billion for the entire Malaysian population.50,51
Pathophysiology of Functional
Dyspepsia: All Bets Are On
Although the presence of FD does not reduce life
expectancy it may impact significantly on an individual
sufferer’s quality of life.52,53 Thus efforts continue to
understand the pathophysiology of this common
affliction.
FD is undoubtedly a heterogeneous disorder and the
various symptoms associated with the disorder may well
be initiated or perpetuated by diverse pathophysiological
mechanisms (Figure 1). For decades the focus, under-
standably, was on the stomach as the likely origin of
symptoms; more recently, the possibility that these same
symptoms could arise from the duodenum and else-
where has gained currency.
Delayed Gastric Emptying
Traditionally, delayed gastric emptying was thought
to be one of the main players in the pathophysiology of
FD. Various studies reported a prevalence of delayed
470 Koduru et al
Figure 1. Schematic representation of the various factors that may be involved in the pathophysiology of FD. Not included in
the figure: diet and lifestyle factors (eg, tobacco, alcohol, nonsteroidal anti-inflammatory drug use), and impact of psychosocial
factors, such as stress, anxiety, and depression.
gastric emptying ranging from 20% to 50% among
dyspepsia sufferers.54 Overall, gastric emptying of solids
was 1.5 times slower than control subjects and signifi-
cantly delayed emptying noted in 40%.55 A source of
major clinical and therapeutic confusion emanates from
the overlap in symptomatology between the PDS subtype
of dyspepsia and so-called idiopathic gastroparesis.56
Furthermore, the relationship between gastric
emptying delay and most FD symptoms remains unclear,
because similar symptoms have been recorded among
patients with normal gastric emptying. The one excep-
tion seems to be post-prandial fullness; studies have
shown with reasonable consistency an association be-
tween delayed gastric emptying and this symptom.54 To
confuse matters further rapid emptying has been
observed in a small proportion of patients with PDS-type
FD and, in this subgroup, correlated with symptom
severity.57
Gastric Accommodation
Gastric accommodation is mediated by a vasovagal
reflex initiated by food ingestion and generated via the
activation of nitrergic nerves that relax the fundus and
Clinical Gastroenterology and Hepatology Vol. 16, No. 4
upper body of the stomach.58 An antrofundic reflex,
relaxation of the fundus in response to antral distention,
also contributes to accommodation.59 Tack et al60 iden-
tified impaired gastric accommodation in 40% of their
FD patients; early satiety alone (reported by 90% of
those with impaired accommodation) proved predictive
of the presence of impaired accommodation. Others have
failed to reproduce this relationship between proximal
gastric function and symptom pattern.61
Several approaches to the assessment of gastric
accommodation (and, simultaneously, sensation) have
been developed and evaluated in humans. Of these, the
barostat is considered the gold standard.62 This involves
the placement, under fluoroscopic guidance, of a poly-
ethylene balloon connected to a barostat device in the
fundus.63 Although the test has excellent reproducibility
it is not used in clinical practice because of the invasive
nature of the procedure and interference with normal
gastric physiology.64 Several less invasive methodologies
that have been explored, such as drink challenge tests
using either water or nutrient, offer an apparently sim-
ple, yet physiological alternative. In the water load test
the patient drinks water until he or she becomes full; the
volume at which maximum satiety is reached is regarded
April 2018
as a surrogate marker for gastric accommodation.65 FD
patients ingest considerably lower volumes and experi-
ence greater severity of symptoms.65 A nutrient drink
test produced similar findings in relation to volume
tolerated and symptoms generated in FD; indeed, caloric
density was not a determinant of the maximum tolerated
volume.66,67 Correlations between results of drink chal-
lenge tests and barostat measurements in the assess-
ment of gastric accommodation have not, unfortunately,
been consistent.66,67 Others, using either conventional
2-dimensional or the more sophisticated 3-dimensional
imaging technique, have used abdominal ultrasonogra-
phy to provide noninvasive measurements of gastric
accommodation.68 Ultrasonography has the additional
advantage of permitting simultaneous measurements of
other parameters of gastric motility including gastric
emptying. There are limitations, however, which include
operator expertise, and technical challenges posed by
anatomic structures and gas interposition.69
Single-photon emission computed tomography
involves imaging of the gastric wall by a single-photon
emission computed tomography gamma camera
following the intravenous administration of 99m Tc
pertechnetate; this approach provides assessments of
gastric volume and its response to a meal.70 Studies
comparing correlation of single-photon emission
computed tomography with barostat showed variable
results; utility in clinical practice has also been limited
by radiation exposure and the need to perform the test
in the supine position.71 Although magnetic resonance
imaging techniques provide accurate measurements of
gastric volumes and gastric emptying rate without any
radiation exposure their application has been limited to
a few research centers because of access to scanning
time, expense, prolonged imaging times, and the need to
perform the study in the supine position.72
Gastric Hypersensitivity
Gastric barostat studies revealed that patients with
FD had lower thresholds for first perception, discomfort,
and pain during distention of the proximal stomach.73,74
Hypersensitivity to gastric distention has been docu-
mented in 34% of FD patients and associated with
postprandial epigastric pain, belching, and weight loss.75
Hypersensitivity in the post-prandial period seems to be
especially discriminating for FD.58 Some,76 but not
others,77 have also noted that epigastric pain is prevalent
among those with hypersensitivity. In further support of
the importance of this phenomenon Vandenberghe
et al78 demonstrated the upregulation of multimodal
afferent pathways in FD.
Duodenal Hypersensitivity to Acid
That the duodenum might play a role in the genesis of
FD symptoms was first suggested by a study that showed
Dyspepsia - A Review 471
that 59% of patients with FD developed nausea during a
brief period of duodenal acid perfusion; the same stim-
ulus failed to induce any symptoms in healthy control
subjects.79 Subsequently, FD patients were shown to
demonstrate an impaired duodenal motor response to
acid perfusion, resulting in reduced clearance of exoge-
nously administered acid from the duodenal bulb.80 This
explains the increased prevalence of spontaneous
duodenal acid exposure during the daytime and after
meals in FD subjects with the most severe symptoms
occurring among those patients with abnormally high
levels of spontaneous duodenal acid exposure.81 Others
noted a correlation between an inability to finish a meal
and lower duodenal pH values.82 It is unclear whether
duodenal acid exposure provokes symptoms directly via
duodenal receptors and sensory nerves or indirectly
through feedback changes in proximal gastric
function.82–85
Duodenal Sensitivity to Lipids
Dyspeptic symptoms are commonly induced by the
consumption of fatty foods.86 In FD, in contrast to control
subjects, intraduodenal infusion of lipids sensitized the
stomach to distention and provoked symptoms of full-
ness, discomfort, and nausea.87 The involvement of
cholecystokinin in this response is suggested by the
ability of the CCK receptor antagonist desloxiglumide to
prevent lipid- and distention-induced dyspeptic
symptoms.88
Postinfectious Functional Dyspepsia
In a manner analogous to postinfectious IBS (PI-IBS)
several studies have identified the de novo development
of FD following an enteric infection.89 In 1 survey, 17%
of patients with FD thought that their symptoms were PI
in origin.90 These individuals had more prevalent early
satiety, nausea, and weight loss; symptoms were attrib-
uted to impaired accommodation resulting from
dysfunction of gastric nitrergic neurons.90 In a prospec-
tive 1-year follow-up study following food-borne
Salmonella enteritis the relative risk for the develop-
ment of FD was 5.2 for exposed individuals with the
occurrence of abdominal pain and vomiting during an
acute attack being identified as positive predictive.91
Indeed, in this study, the likelihood of developing PI-FD
was greater than that of PI-IBS. Giardia lamblia infec-
tion has been shown to provoke visceral hypersensitivity
and delay gastric emptying.92
Inflammation and Immune Activation
In a manner analogous to IBS, several studies have
explored the role of inflammatory pathways in FD. In
comparison with those with FD in general, subjects with
PI-FD were more likely to exhibit focal aggregates of
472 Koduru et al
T cells and CD8þ cells in the duodenum with gastric
emptying being slower among those patients with focal
aggregates. The number of CD4þ cells per crypt was
reduced, whereas the number of macrophages sur-
rounding crypts was increased in PI-FD.93 In a related
study histologic duodenitis, characterized by inflamma-
tory cells and macrophages, was found to be more
prevalent in PI-FD in comparison with healthy volun-
teers; furthermore, the symptom of epigastric burning
correlated with the degree of duodenitis.94
Inflammation may not confined be to PI-FD. Although
the number of mast cells was increased in all FD suf-
ferers, the number of enterochromaffin cells was signif-
icantly higher in PI-FD than in either those with
nonspecific FD or in healthy control subjects.95
Augmented expression of histamine, serotonin, and
tryptase in gastric mucosal biopsy samples has also been
identified in FD and, of potential pathophysiological
importance, observed to occur in close proximity to
nerves in patients with PI-FD.95 Systemic immune acti-
vation has also been observed, as evidenced by increased
levels of peripheral blood mononuclear cells, tumor
necrosis factor-a, interleukin-1b and -10, and gut-homing
T cells. Each correlated with various FD symptoms.96
Duodenal Eosinophilia
In a study of 51 FD subjects and 48 healthy control
subjects, Talley et al97 found that the odds ratio for the
presence of FD in subjects with high duodenal bulb
eosinophil counts was 11.7. Of note, gastric eosinophilia
was not evident and the symptom of early satiety was
associated with duodenal eosinophilia after adjusting for
age, sex, and H pylori status.97 The same group has now
confirmed this association in children.98 Duodenal
eosinophilia has also been observed in PI-FD94 and, in
some studies, associated with mast cell infiltration.99 The
presence of duodenal eosinophilia has also been associ-
ated with allergy and the PDS subtype of FD,100 sug-
gesting that a hypersensitivity to luminal contents may
be involved.100 In a subsequent study it was noted that
duodenal eosinophilia was evident in the second part of
duodenum in subjects experiencing early satiety and
post-prandial fullness, whereas abdominal pain was
associated with eosinophilia in both the bulb and second
part of duodenum.101
Helicobacter pylori Infection
It has long been assumed that H pylori–related
gastritis could cause dyspeptic symptoms via a variety of
disturbances in acid secretion, motility, and neuroendo-
crine signaling102–104; although multiple pathways could
be involved, their relative roles in the genesis of
dyspeptic symptoms in FD related to H pylori remain to
be defined. In relation to motility, infection with
H pylori has been linked to increased expression of
Clinical Gastroenterology and Hepatology Vol. 16, No. 4
glucagon-like-peptide-1 and accelerated gastrointestinal
transit in 1 animal model105; in patients with FD,
however, the presence of H pylori infection did not seem
to affect gastric emptying rate.106 Although H pylori
infection does not seem to influence gastric accommo-
dation,107 studies in FD107 and IBS108 suggest that it may
trigger visceral, including gastric, hypersensitivity; a
highly plausible hypothesis given the known effects of
inflammation on visceral sensation.109
Psychosocial Factors
It has been recognized for decades that FD is
commonly linked with psychological comorbidities, such
as anxiety and depression.110 Comorbid anxiety and
depression are thought to not only contribute to the
basic pathogenesis of symptoms in some FD sufferers,
but also to drive health care–seeking behavior.110 Func-
tional brain imaging studies have examined gut-brain
interactions, the processing of these signals and their
interactions with various parts of the brain and their
circuitry in FD and generated plausible explanations for
the roles of emotion, stress responses, and psychological
processes and psychiatric comorbidity in FD.110,111
Indeed, Van Oudenhove et al110 have proposed an inte-
grated model of FD as a disorder of gut-brain signaling,
analogous to IBS.95 Interestingly, somatization seems to
be equally common in subjects with either FD or organic
dyspepsia.112
Other Associations
FD, along with other functional gastrointestinal dis-
orders, has been linked to the joint hypermobility syn-
drome (Ehlers-Danlos type III); the basis for this
association is unknown.113
Management of Functional Dyspepsia:
the Challenges Persist
The first step in the management of a patient with FD
is to reassure him or her of the nonfatal nature of the
disease.114 In so doing one must not belittle the seri-
ousness of the sufferer’s complaints but rather devote
time to understanding the true nature of their symptoms
and their impact on daily life.
Diet
Visceral adiposity has been associated with an
increased risk of FD.115 Consumption of canned food and
use of alcohol weekly have been associated with the in-
duction of FD symptoms.116 Diets high in fat and salt
have also been associated.117 Because of the overlap
between IBS and FD, fermentable oligosaccharides, di-
saccharides, monosaccharides, and polyols may well be
relevant to symptom development in FD.117 Other
April 2018
studies have shown that dyspeptic symptoms are trig-
gered by carbonated drinks and hot spices.118
Antidepressants
Based on the aforementioned prevalence of comorbid
psychological distress among patients with FD, and on
their effects on gastrointestinal physiology, there has
been considerable enthusiasm for the use of antide-
pressants in this disorder.110,119,120 However, evidence
for therapeutic benefit for antidepressant therapy in FD
has been mixed.121,122 A meta-analysis comparing the
efficacy and safety of selective serotonin reuptake in-
hibitors and tricyclic antidepressants found that tricyclic
antidepressants, but not selective serotonin reuptake
inhibitors, were effective in alleviating symptoms in
FD.121 A recently updated meta-analysis came to similar
conclusions; here benefit was limited to antipsychotics
and tricyclic antidepressants and to those who had a
coexistent mood disorder.122 In a comparative study,
amitriptyline, 50 mg daily, was more effective than
escitalopram, 10 mg, or placebo daily over 10 weeks.123
Those with ulcer-like epigastric pain and normal gastric
emptying were most likely to respond to amitripty-
line.123 In keeping with this finding, nortriptyline, in
another study, failed to improve symptoms in idiopathic
gastroparesis.124
Eradication of Helicobacter pylori
Eradication of H pylori has been shown to lead to a
small (10%) but significant improvement in symptoms
with FD.46–48 In 1 meta-analysis, improvements in
dyspepsia symptoms were greater in the treatment
group (odds ratio, 1.38) 1 year later with symptom
improvement rates at 3 months being predictive of
improvement at 1 year.125 Males and those with a higher
body mass index were more likely to respond.126 There
was no symptomatic advantage for sequential therapy
over standard triple therapy; eradication rates were also
similar.127 Whether the addition of bismuth subsalicylate
to standard triple therapy128 would provide additional
benefits in FD has yet to be established.
These results notwithstanding, the critical question is
how the “test-and-treat” approach, a long-time staple in
the management of dyspepsia, stacks up against other
management strategies. When compared with “test-and-
treat,” prompt endoscopy has been associated with a
small, but significantly greater, benefit in terms of
symptom outcomes, although at a greater expense.129,130
When test-and-treat was compared with empiric proton
pump inhibitor, there were no significant differences in
symptoms or costs at 12 months.130,131 Not surprisingly
benefits from eradication increased in parallel with the
prevalence of H pylori131; where it is greater than 10% to
20%, test-and-treat is more cost-effective than empiric
proton pump inhibitor therapy.130
Dyspepsia - A Review 473
Prokinetic Agents
The most widely used prokinetics in the United
States, metoclopramide and domperidone (although not
approved in the United States, it is commonly sourced
from Mexico and Canada), have never been shown
convincingly to be effective of FD. A meta-analysis of the
selective 5-HT4 receptor agonist, mosapride, failed to
identify any benefit.132 Cinitapride, a 5-HT4 agonist and
D2 antagonist, was compared with domperidone in PDS;
although rates of overall symptom relief were similar at
85.8% versus 81.8%, respectively, cinitapride produced
greater decreases in the severity of post-prandial full-
ness, early satiation, and bloating.133
Itopride is a novel prokinetic agent that inhibits
acetylcholinesterase and is a dopamine D2 receptor
antagonist. In a meta-analysis involving 2620 patients,
itopride resulted in superior rates of global assessment
of dyspepsia symptoms.134 Behind this meta-analysis lies
a more complex and instructive story. Considerable
enthusiasm for itopride in FD was generated by a phase
II study that demonstrated significant symptomatic
benefit.135 Unfortunately, 2 phase III randomized
controlled trials, 1 international and 1 North American,
failed to confirm these findings.136 This stark difference
in outcomes was thought to have resulted from a subtle
difference in study populations; the phase II study was
liberal in its inclusion of subjects with heartburn,
whereas the phase III studies were much more restric-
tive and a reanalysis of the phase II study found that
most of the benefits attributable to the drug were found
among those with significant heartburn.135,136 These
observations serve as a timely reminder of how the
precise nature of a given study population can influence
response to therapy.
Acotiamide, a muscarinic antagonist and acetylcho-
linesterase inhibitor, was shown to improve FD symp-
toms in several phase II trials and proceeded to a large,
multicenter phase III study in Japan among patients with
PDS-predominant FD.137 The elimination rates of 3 meal-
related symptoms (post-prandial distress, upper
abdominal bloating, and early satiation) were higher in
the acotiamide group (15.3%) than in placebo (9.0%).137
In a subsequent 48-week open-label extension symptom
relief rates for these symptoms remained stable at 13%
from 8 weeks onward.138 Studies are currently under-
way in Europe and the United States to assess efficacy
and safety in other ethnicities.
Enhancing Gastric Accommodation
Buspirone, an antidepressant that is a serotonin
5-HT1A receptor partial agonist and, thus, may facilitate
relaxation of the gastric fundus and body, significantly
reduced overall symptom severity and that of post-
prandial fullness, early satiety, and upper abdominal
bloating, without an appreciable increase in adverse
events, in FD.139
474 Koduru et al
Nonpharmacologic Therapies
In both the short (10 weeks) and longer (6 months)
psychotherapy was shown to provide additive benefit to
conventional medical therapy140; psychodynamic
therapy has also proven to increase the symptomatic
response H pylori eradication.141 Although these
approaches seem promising, their cost effectiveness
remains to be evaluated. Acupuncture, according to 1
meta-analysis of 20 trials of performed in Asia, is supe-
rior to placebo or standard interventions.142 These
studies, however, had a high risk of bias; other studies
have shown that gastrointestinal-specific acupuncture is
superior to nonspecific acupuncture in the treatment
of FD.143
More than 44 herbal preparations have been studied
and reported to be of benefit in the treatment of
FD.144,145 Various studies have evaluated the efficacy of
herbal extracts in the treatment of FD. In a recent meta-
analysis of the herbal preparation STW5 (Iberogast;
Steigerwald Arneimittelwerk GmbH, Darmstadt, Ger-
many) it was found that, in comparison with placebo,
patients receiving Iberogast enjoyed a significantly
greater improvement in their symptoms after 4 weeks of
treatment.146 Rikkunshito, a ghrelin enhancer, has been
studied in several clinical trials, and has also been shown
to be superior to placebo in FD and seems to be espe-
cially effective in addressing epigastric pain and post-
prandial fullness.147 Although ginger has been shown to
accelerate gastric emptying in patients with FD, there
was no impact on gastrointestinal symptoms; however,
small study population sizes complicate interpreta-
tion.148 Menthacarin, a peppermint/caraway oil combi-
nation, administered for 2 weeks, has been shown to
improve quality of life and symptoms in both the EPS
and PDS subgroups of FD.149
Clinical Gastroenterology and Hepatology Vol. 16, No. 4
Novel Approaches
In a small study that used positron emission tomog-
raphy to target the cannabinoid-1 receptor, patients with
FD were found to have higher cannabinoid-1 receptor
availability in the cerebral regions involved in visceral
nociception and the homeostatic regulation of food
intake.150 Although these findings need to be replicated
in larger samples, they suggest that the cannabinoid-1
receptor could serve as a novel target in FD.
Dyspepsia: a Clinical Guide
Dyspepsia presents a formidable challenge for the
clinician. How to make sense of the multiplicity of pro-
posed pathophysiologic mechanisms and profusion of
(for the most part) marginally effective therapeutic op-
tions? Figure 2 provides a simplified approach to the
patient presenting for the first time with dyspeptic
symptoms. The evidence in support of the main man-
agement options has already been presented but can be
summarized as follows. Their shortcomings notwith-
standing, one should first seek to identify alarm features
(red flags); their presence in the right context (age,
ethnicity, prior disease) should prompt a search for
organic disease, a strategy that usually begins with
endoscopy. In the absence of alarm symptoms and in an
individual or population where the presence of H pylori
is likely, “test and treat” is a cost-effective approach; if
H pylori prevalence is low and reflux-type symptoms are
prominent,151 an empiric trial of a proton pump inhibitor
should be considered. Failure should prompt endoscopy
but do not expect to find a lot. Once these options have
been exhausted what comes next? Right now the proki-
netic cupboard is pretty bare in the United States;
metoclopramide carries a black box warning and is
Figure 2. Suggested
approach to the assess-
ment and management of
dyspepsia. Note that
endoscopy must take
account of prior therapy.
April 2018
limited to short courses of treatment and none of the
other prokinetics are currently available. Other off-label
approaches should be considered, such as tricyclic anti-
depressants and buspirone. My own preference is to opt
for the former if pain dominates and the latter if
post-prandial fullness and/or early satiety are more
problematic. Along the way, attention must be paid to
comorbid psychopathology and overlap with other
functional gastrointestinal disorders, such as IBS and
constipation; relieving constipation may substantially
improve upper gastrointestinal symptoms. For resistant
and disabling symptoms, consider nonpharmacologic
approaches, such as psychotherapy or acupuncture, if a
skilled therapist is available.
Conclusions
In describing dyspepsia “as a disease space of unde-
termined dimensions occupied by many conditions that
share a more or less common core of symptoms, some of
which may coexist,” Crean et al5 aptly summarized the
challenge this symptom complex presents: protean
manifestations, causes, and potential therapies. It is no
wonder that “we find it difficult to define”5 and manage.
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Reprint requests
Address requests for reprints to: Eamonn M. M. Quigley, MD, 6550 Fannin Street,
SM 1201, Houston, Texas 77030. e-mail: equigley@houstonmethodist.org; fax:
(713) 797-0622.
Acknowledgments
Dedicated to the memory of Gerard Patrick Crean, MB PhD (1927–2005);
scientist, gastroenterologist, teacher, and mentor.
Conflicts of interest
The authors disclose no conflicts.