SPECIAL REPORTS AND REVIEWS Pathophysiology and Treatment of Functional Dyspepsia

Transcription

GASTROENTEROLOGY 2004;127:1239 –1255
SPECIAL REPORTS AND REVIEWS
Pathophysiology and Treatment of Functional Dyspepsia
JAN TACK, RAF BISSCHOPS, and GIOVANNI SARNELLI
Division of Gastroenterology, Department of Internal Medicine, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium
yspeptic symptoms, defined as discomfort or pain in
the upper part of the abdomen, occur very commonly
in the general population. Epidemiologic surveys suggest
that 15%–20% of the general population in Western countries experience dyspepsia over the course of 1 year.1,2 Despite the fact that only about 1 in 4 people with dyspeptic
symptoms choose to consult a physician,1 dyspepsia is a
clinical problem of considerable magnitude for the health
care system due to the high prevalence and the chronic or
recurrent nature of symptoms.3
Most of these patients have no identifiable cause of dyspepsia by standard diagnostic tests,4 which is referred to as
functional dyspepsia. According to international consensus,
the definition of functional dyspepsia is persistent or recurrent pain or discomfort centered in the upper abdomen
without evidence of organic disease likely to explain the
symptoms (Table 1).5 Discomfort refers to unpleasant sensations that the subject does not interpret as pain and may
be characterized by upper abdominal fullness, early satiety,
bloating, belching, or nausea. Furthermore, there is no
relation between dyspeptic symptoms and bowel movements (i.e., irritable bowel syndrome does not explain the
symptoms), and patients with predominant heartburn
should be excluded.5
D
The Dyspepsia Symptom Complex
The symptom complex includes epigastric pain,
bloating, early satiety, fullness, epigastric burning,
belching, nausea, and vomiting. Although often chronic,
the symptoms in functional dyspepsia are frequently
intermittent, even during a period with marked symptoms.6 In patients with functional dyspepsia seen at a
tertiary referral center, the most prevalent symptoms
were postprandial fullness and bloating, followed by
epigastric pain, early satiety, nausea, and belching.7–11
However, there is considerable heterogeneity as shown,
for instance, in the number of symptoms that patients are
reporting (Figure 1). In the general population, the most
prevalent dyspeptic symptoms are postprandial fullness,
early satiety, upper abdominal pain, and nausea.12,13
Attempts have been made to simplify the intricate heterogeneity of the dyspepsia symptom complex. The Rome
II committee proposed a subdivision according to the predominant symptom of either pain or discomfort (Table 1).
Studies have shown correlations between this subdivision
and the presence of Helicobacter pylori infection or delayed
gastric emptying14 and between this subdivision and response to acid-suppressive therapy.15 However, the subdivision has also been criticized because of the significant
overlap between the symptom subgroupings, the considerable number of patients who do not fit into one of the
subgroups, and, above all, the lack of adequate value in
predicting underlying organic disease.2,16
A factor analysis of dyspeptic symptoms in tertiary care
patients did not support the existence of functional dyspepsia as a homogeneous (unidimensional) condition. A 4-factor model (nausea/vomiting/satiety/weight loss, bloating/
fullness, pain/burning, and belching) was found to be valid,
with differential distribution within the patient population
according to cluster analysis.17 In the general population,
factor analysis identified 2 factors (early satiety/fullness/pain
and nausea/vomiting), with differential distribution within
the population according to cluster analysis.13 These studies
confirm the heterogeneity of the dyspepsia symptom complex, but there is no proof that these provide a clinically
meaningful subdivision of the syndrome.
Dyspeptic symptoms are often aggravated by food
ingestion. Studies using questionnaires showed that
⬎75% of dyspeptic patients report a relationship between aggravation of symptoms and ingestion of a
meal.18,19 Registration of symptoms before and after
ingestion of a standardized meal showed that dyspeptic
symptoms increase with meal ingestion in ⬎90% of
dyspeptic patients and that maximum symptom severity
Abbreviations used in this paper: 5-HT, 5-hydroxytryptamine; PPI,
proton pump inhibitor; SSRI, selective serotonin reuptake inhibitor.
© 2004 by the American Gastroenterological Association
0016-5085/04/$30.00
doi:10.1053/j.gastro.2004.05.030
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TACK ET AL.
Table 1. Definition of Functional Dyspepsia and Subgroups
According to the Rome II Working Committee5
Definition of functional dyspepsia, according to the Rome II working
team:
At least 12 weeks (which need not be consecutive), within the
preceding 12 months, of the following:
Persistent or recurrent pain or discomfort centered in the
upper abdomen;
No evidence of organic disease (including upper endoscopy)
that is likely to explain the symptoms; and
No evidence that the dyspepsia is exclusively relieved by
defecation or associated with the onset of a change in stool
frequency or stool form (i.e., not irritable bowel syndrome)
Dyspepsia subgroups based on the predominant or most
bothersome symptoms, according to the Rome II working
team:
Ulcer-like dyspepsia
Pain centered in the upper abdomen is the predominant (most
bothersome) symptom
Dysmotility-like dyspepsia
An unpleasant or troublesome nonpainful sensation
(discomfort) centerd in the upper abdomen is the
predominant symptom; this sensation may be characterized
by or associated with upper abdominal fullness, early
satiety, bloating, belching, or nausea
Unspecified dyspepsia
Cannot be classified as above
GASTROENTEROLOGY Vol. 127, No. 4
Delayed Gastric Emptying
Delayed gastric emptying is traditionally considered
a major pathophysiologic mechanism underlying symptoms
in functional dyspepsia and idiopathic gastroparesis.7,11,20 –29 Several studies have investigated the relationship between delayed gastric emptying and symptom pattern and severity. Depending on the study, the percentage
of dyspeptic patients with delayed gastric emptying ranges
from 20% to 50%.7,11,20 –29 In a meta-analysis of 17 studies
involving 868 dyspeptic patients and 397 controls, significant delay of solid gastric emptying was present in almost
40% of patients with functional dyspepsia.23 However,
most of the studies were performed in small groups of
patients and small control groups. In the largest studies,
gastric emptying of solids was delayed in about 30% of the
patients with functional dyspepsia.7,11,27–29
Most studies failed to find a convincing relationship
between delayed gastric emptying and symptom pattern.20 –22 More recently, 3 large-scale single-center studies
showed that patients with delayed gastric emptying for
occurs between 45 and 90 minutes after ingestion of a
standardized 250-kcal meal.18,19
Weight loss is traditionally considered an alarm symptom, pointing toward diagnoses other than functional
dyspepsia. Recent studies in tertiary care patients reported the presence of weight loss as a symptom associated with functional dyspepsia,8 –11 but this was considered to reflect the situation in tertiary care only.
However, more recent, preliminary observations in the
general population also report an association between
dyspeptic symptoms and weight loss.13
Pathophysiologic Mechanisms and
Their Relation to Symptom Pattern
Several pathophysiologic mechanisms have been
suggested to underlie dyspeptic symptoms. These include delayed gastric emptying, impaired gastric accommodation to a meal, hypersensitivity to gastric distention, H. pylori infection, altered response to duodenal
lipids or acid, abnormal duodenojejunal motility, or
central nervous system dysfunction (Figure 2). At
present, the pathophysiology of functional dyspepsia is
only partially elucidated. However, there is growing
evidence that functional dyspepsia is in fact a very heterogeneous disorder and different subgroups can be identified based on different demographic, clinical, and
pathophysiologic features.7–11
Figure 1. Symptom pattern in patients with functional dyspepsia
seen at a tertiary referral center. (A) Percentage of dyspeptic symptoms rated as moderate or severe (scores 2 and 3 on a scale of 0 –3)
in 640 patients with functional dyspepsia seen at a tertiary referral
center. (B) Prevalence of the number of symptoms that are rated as
moderate or severe (scores 2 and 3 on a scale of 0 –3) in 640
patients with functional dyspepsia seen at a tertiary referral center.
October 2004
Figure 2. Normal fasting and postprandial gastric function; pathophysiologic mechanisms putatively involved in functional dyspepsia.
solids are more likely to report postprandial fullness, nausea,
and vomiting,7,11,28 although a large multicenter study
failed to find any association29 (Table 2). Almost all studies
focused on solid emptying rate only. A recent large-scale
study suggested an association between delayed emptying
for liquids and symptoms of postprandial fullness.11
Impaired Gastric Accommodation to a Meal
The motor functions of the proximal and distal
stomach differ remarkably. Whereas the distal stomach
regulates gastric emptying of solids by grinding and
sieving the content until the particles are small enough
to pass the pylorus, the proximal stomach serves mainly
as a reservoir. Accommodation of the stomach to a meal
consists of a relaxation of the proximal stomach, providing the meal with a reservoir and enabling an increase in
volume without an increase in pressure.
Scintigraphic and ultrasonographic studies have shown
an abnormal intragastric distribution of food in patients
with functional dyspepsia, with preferential accumulation
in the distal stomach.22,30 –33 These findings suggest defective postprandial accommodation of the proximal stomach.
Consistently, studies using a gastric barostat have shown
reduced proximal gastric relaxation in response to a meal in
patients with functional dyspepsia.8,34 Insufficient accommodation of the proximal stomach during and after the
ingestion of a meal may be accompanied by increased
intragastric pressure and activation of mechanoreceptors in
the gastric wall, thus inducing symptoms.
Using a gastric barostat in 40 consecutive dyspeptic
patients, we showed that impaired gastric accommodation was present in 40% of the patients and that this
impairment was associated with symptoms of early satiety and weight loss.8 The relation between impaired
FUNCTIONAL DYSPEPSIA
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gastric accommodation and early satiety was also apparent from the correlation between the amplitude of the
meal-induced relaxation and the amount of calories ingested at maximum satiety in patients with early satiety.8 Others, using single-photon emission computed
tomography, scintigraphy, or barostat studies of the
proximal stomach, have confirmed the prevalence of impaired accommodation in approximately 40% of dyspeptic patients, but the relationship with symptom pattern
has been found to be less consistent (Table 3).35–37
An unsolved issue is the site of symptom generation in
patients with impaired accommodation. When the proximal stomach is not relaxing properly, ingestion of a
meal may be accompanied by activation of tension mechanoreceptors in the proximal stomach wall and generation of symptoms. On the other hand, insufficient accommodation of the proximal stomach may force the
meal into the distal stomach, thereby creating a distended antrum. Studies on the induction of symptoms
during proximal and distal gastric distention in humans
have shown conflicting results38 – 40 that are at least partly
attributable to technical and methodological differences.
The gold standard for assessment of gastric sensitivity to
distentions is currently the gastric barostat; however,
instead of dual barostat distentions, these studies used
ultrasound measurements or single water-filled or
barostat balloons. In a recent study using a double gastric
barostat assembly, we showed that symptom profiles
induced by gastric distention did not differ between
Table 2. Prevalence of Delayed Emptying and Relationship
With Symptoms in Functional Dyspepsia in
Literature Studies
n
Prevalence
of delayed
emptying
(%)
Wegener et al., 198920
Jian et al., 198921
Talley et al., 198922
Waldron et al., 199123
Klauser et al., 199324
Scott et al., 199325
Stanghellini et al.,
19967
43
28
32
50
69
75
343
30
59
30
42
35
28
34
Maes et al., 199727
Perri et al., 199828
344
304
30
33
Sarnelli et al., 200311
392
23
Talley et al., 200129
551
24
Study
Correlation
No correlation
No correlation
No correlation
No correlation
No correlation
No correlation
Associated with female
sex, postprandial
fullness, vomiting
Not studied
Associated with
postprandial
fullness, nausea,
and vomiting
Associated with
postprandial
fullness, nausea,
and vomiting
No correlation
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TACK ET AL.
Table 3. Prevalence of Impaired Accommodation and Relationship With Symptoms in Functional Dyspepsia in Literature
Studies
n
Technique
Tack et al., 19988
Kim et al., 200135
Study
40
32
Boeckxstaens et al., 200236
Piessevaux et al., 200337
44
40
Barostat
Single-photon emission computed
tomography
Barostat
Scintigraphy
aThe
Prevalence of
impaired
accommodation (%)
Correlation
40
40
Early satiety, weight loss
Weight lossa
40
50
No correlation
Early satiety
symptom of early satiety was not assessed in this study.
proximal and distal gastric distention and that mechanoreceptors from both sites may contribute to symptoms.41
However, because the distal gastric wall is less compliant
than the proximal gastric wall, the distal stomach may
produce greater symptoms in response to the same volume of distention.41
Hypersensitivity to Gastric Distention
Physiologic stimuli during the digestive process
are not normally perceived but in some circumstances
may induce conscious sensations. During the past decade,
it has been suggested that patients with functional gastrointestinal diseases may have a sensory dysfunction of
the gut, so that physiologic stimuli would induce symptoms.42 Several studies have clearly established that, as a
group, patients with functional dyspepsia have enhanced
sensitivity to gastric distention.9,36,43– 46 However, in
these studies, different approaches to calculate sensitivity
to gastric distention and to determine the range of
normality have been used.
A systematic analysis in a large group of controls and
patients indicated that the increase in the intra-balloon
pressure over intra-abdominal pressure needed to induce
discomfort or pain is the most appropriate expression of
sensitivity to gastric distention.9 According to that study,
gastric hypersensitivity was associated with symptoms of
postprandial pain, belching, and weight loss. So far, other,
smaller-scale studies have failed to find an association between hypersensitivity and symptom pattern (Table 4).36,47
Perception of gastric distention requires the activation
of mechanoreceptors, and studies in healthy volunteers
have suggested involvement of “in series” mechanoreceptors that respond to increases in tension within the
stomach wall.48,49 By analyzing the relationship between
changes in perception and increases in pressure in an
isovolumetric balloon in the proximal stomach, we were
able to show that dyspeptic patients with hypersensitivity to gastric distention perceive isovolumetric phasic
contractions of the proximal stomach.50 Fundus-relaxing
drugs decrease sensitivity to gastric distention and de-
crease meal-induced symptoms in these patients.50 These
findings are compatible with involvement of tension
mechanoreceptors in the symptom generation in dyspeptic patients with visceral hypersensitivity.
Because patients with hypersensitivity to gastric distention have more prevalent symptoms of epigastric
pain9,17 and because they experience pain during gastric
balloon distention at levels of distention that are normally not painful, these patients have visceral hyperalgesia.43– 45 According to the neurophysiologic theory of
pain, pain can be encoded by activation of high-threshold
nociceptive pathways or by intense stimulation of lowthreshold multimodal pathways.51 To determine whether
gastric hypersensitivity in functional dyspepsia reflects a
selective sensitization for painful sensations or whether
the sensitivity for nonpainful stimuli is also enhanced in
patients with visceral hypersensitivity, we analyzed the
relationship between intensity scores for pain and nonpainful sensations during gastric balloon distention in
dyspepsia.52 In both normosensitive and hypersensitive
dyspeptic patients, the elevation of intensity scores for
pain paralleled the elevation of intensity scores for the
nonpainful sensations of nausea, satiety, and fullness.
These findings are compatible with up-regulation of
multimodal afferent pathways and argue against isolated
up-regulation of pain-specific afferent pathways in functional dyspepsia with visceral hyperalgesia.
Table 4. Prevalence of Hypersensitivity to Gastric Distention
and Relationship With Symptoms in Functional
Dyspepsia in Literature Studies
n
Prevalence of
hypersensitivity
(%)
46
Mertz et al., 1998
Rhee et al., 200047
Tack et al., 20019
24
64
160
66
50
34
Boeckxstaens et al.,
200236
44
48
Study
Correlation
No correlation
No correlation
Pain, belching,
weight loss
No correlation
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Table 5. Literature Studies on Duodenal Hypersensitivity in Functional Dyspepsia
Study
68
Barbera et al., 1995
Barbera et al., 199567
Samsom et al., 199971
Feinle et al., 200166
n
Technique
Conclusion
10 patients
10 controls
9 patients
9 controls
Duodenal lipid infusion, duodenal saline
infusion, gastric balloon distention
Duodenal lipid infusion, duodenal
glucose infusion, gastric balloon
distention
Duodenal acid infusion, duodenal
manometry and pH monitoring
Duodenal lipid infusion, gastric balloon
distention, CCK-A antagonist
Duodenal lipids sensitize the stomach to distention
in patients with dyspepsia but not in controls
Duodenal lipids but not glucose sensitize the
stomach to distention in dyspepsia
12 patients
10 controls
12 patients
Acid clearance is decreased in dyspepsia;
hypersensitivity to duodenal acid induces nausea
CCK-A receptors are involved in sensitization by
duodenal lipids
CCK, cholecystokinin.
Dyspeptic symptoms are usually triggered or aggravated
by meal ingestion, suggesting that sensitivity to gastric
distention in the postprandial period might be involved in
symptom generation. In a preliminary study, we showed
that postprandial sensitivity to gastric distention, but not
fasting sensitivity, was indeed related to the severity of
meal-related symptoms in functional dyspepsia.53
H. pylori Infection
Soon after the discovery of H. pylori, a causal
relationship between H. pylori infection and the occurrence of duodenal and gastric ulcers was established.51 In
functional dyspepsia, the role of H. pylori is less clear. A
recent systematic review of the epidemiologic evidence
on a relationship between H. pylori infection and functional dyspepsia found no evidence for a strong association. However, according to the investigators, many of
the studies had important weaknesses in design and
execution and there was not enough evidence to rule out
a modest association.55
Several studies have investigated the association between H. pylori infection and dyspeptic symptoms or
pathophysiologic mechanisms.28,56 – 61 However, no consistent differences in the prevalence and severity of individual dyspeptic symptoms, gastric emptying rate, gastric relaxation after a meal, and sensitivity to gastric
distention were found between H. pylori–positive and H.
pylori–negative subjects. Initial studies reported associations between H. pylori infection and epigastric pain or
burning,56 delayed gastric emptying,57 or impaired accommodation.58 However, more recent and larger-scale
studies failed to find any of these correlations.59 – 61
Altered Duodenal Sensitivity to Lipids or
Acid
Dyspeptic symptoms in functional dyspepsia are
commonly exacerbated by meals rich in fat.62 Studies in
health have shown that duodenal infusion of lipids, but
not glucose, induces a relaxation of the proximal stomach
and enhances the sensitivity to proximal stomach disten-
tion.63,64 These influences of duodenal lipid infusion
require lipid digestion and subsequent release of cholecystokinin,64,65 and they can be blocked by administration of a lipase inhibitor or a cholecystokinin-A receptor
antagonist.64 – 66 It was reported that increased sensitivity
to duodenal lipid infusion may be a relevant pathophysiologic mechanism in functional dyspepsia.67,68 However, the numbers of patients studied in this manner
remained small, and it is unclear whether this affects a
subgroup of dyspeptic patients or all dyspeptic patients
(Table 5). Furthermore, all of these studies used intraduodenal mode administration, and recent data have
shown that observations derived from intraduodenally
administered lipids do not necessarily apply to orally
ingested lipid-containing meals.69,70
Duodenal infusion of hydrochloric acid was found to
induce nausea in a small group of patients with functional dyspepsia but not in healthy controls, suggesting
duodenal hypersensitivity to acid. Furthermore, previous
studies have shown that the duodenal motor response to
acid was decreased in patients with functional dyspepsia,
resulting in reduced clearance of exogenous duodenal
acid.71 We confirmed that spontaneous duodenal acid
exposure to endogenous acid was increased in patients
with functional dyspepsia who displayed delayed clearance of exogenous duodenal acid.72 Patients with functional dyspepsia with duodenal acid exposure above the
normal range had higher severity scores of several dyspeptic symptoms. However, the severity of individual
symptoms was weakly correlated to duodenal pH and
brief duodenal acid infusion did not affect any symptoms, suggesting that duodenal acid exposure is poorly
related to symptom severity.72
Altered Antroduodenojejunal Motility
Manometry studies in functional dyspepsia have
shown antral hypomotility to be a common feature.73 It
is presently unclear whether this reflects true hypomotility or a poor registration of contractions in a dilated
antrum in patients with impaired accommodation, be-
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TACK ET AL.
cause manometry only registers lumen-obliterating contractions.8,30 –32,73 Small bowel motor alterations, usually
hypermotility with burst activity or clusters, and an
increased proportion of duodenal retrograde contractions
have been reported.74,75 No clear correlation with symptoms has been found.74,75
Abnormalities of Gastric Electrical Rhythm
There is also evidence that abnormalities in the
underlying gastric myoelectrical activity, as measured by
cutaneous electrogastrography, are found in up to two
thirds of patients with functional dyspepsia.76,77 The
relevance of this finding for gastric emptying and symptom patterns remains to be established. No correlation
was found between dyspeptic symptom pattern and the
presence of findings on electrogastrography. A good correlation between the presence of delayed gastric emptying and abnormalities of gastric electrical rhythm has
been reported.76,77
Unsuppressed Postprandial Phasic
Contractility in the Proximal Stomach
Besides the relaxatory response of the proximal
stomach after a meal, other motor aspects of the proximal
stomach have not been particularly frequently addressed
in the literature. With the barostat technique, it is also
possible to detect phasic volume fluctuations from the
baseline volumes (“volume waves”), reflecting contractions superimposed on the background state of contractility or tone.78 These contractions occur at a frequency
that differs from antral contraction waves.59,78,79 One
study suggested the occurrence of increased phasic volume events in the postprandial period in patients with
functional dyspepsia.59 In a recent study, we observed
that, compared with healthy controls, a small subset
(15%) of dyspeptic patients displayed unsuppressed postprandial phasic contractility of the proximal stomach.79
Persistence of postprandial phasic contractions of the
proximal stomach was associated with H. pylori infection
and relevant or severe bloating, but also with the absence
of nausea. The abnormality is of potential relevance
because phasic fundic contractions induce transient increases in gastric wall tension, which can be perceived in
functional dyspepsia.50
Autonomic Nervous System/Central
Nervous System Dysregulation
Abnormalities within the autonomic nervous system have been suggested to be of importance in some
patients with functional dyspepsia. More specifically, an
efferent vagal dysfunction has been observed in several
studies80,81 and has been proposed to be a possible mech-
anism underlying impaired accommodation to a meal82
and antral hypomotility.80 Furthermore, there is evidence of an association between psychopathology and
functional dyspepsia83 and between psychological factors
and gastric functioning and symptoms in functional
dyspepsia, for which low vagal activity was proposed to
be the mediating mechanism.84,85
In a recent factor analysis of dyspeptic symptoms and
their relationship with physiopathology and psychopathology, the heterogeneity and complexity of these interactions
was clearly shown. Factor analysis identified 4 separate
symptom factors within functional dyspepsia, each of which
was associated with a measurable abnormality of gastric
function, and of which 2 were associated with specific
psychosocial characteristics.17 The factor that consists of
nausea, vomiting, early satiety, and weight loss was associated with female sex and physician visits and sickness leave,
and the factor that consists of epigastric pain was associated
with several psychosocial dimensions, including medically
unexplained symptoms and conditions, and with low
health-related quality of life.17
Relevance of Putative
Pathophysiologic Mechanisms to
Symptom Generation
Although several pathophysiologic abnormalities are
related to the dyspepsia symptom pattern and severity, as
summarized in the previous section, this does not establish
causality. It is conceivable that both simply coexist or that
both depend on a presently unspecified causal mechanism.
A close correlation between presence and severity of a certain pathophysiologic abnormality and presence and severity of certain symptoms adds strength to the association
between both. A very strong case is made when induction of
a pathophysiologic abnormality in healthy subjects also
induces dyspeptic symptoms.
Delayed Gastric Emptying
The studies investigating the relationship between delayed emptying and symptom pattern generally
used questionnaires that assessed symptom severity over
a time frame of weeks to months, whereas the emptying
test reflects the situation at a single point in time. Several
studies have shown that gastric emptying in functional
dyspepsia has large intraindividual variability.19,86 Attempts have been made to find a better correlation between symptoms and emptying rate by assessing symptom severity during the measurement of the emptying
rate of a standardized meal.18,19 However, this did not
result in a better correlation between symptoms and
emptying rate.
October 2004
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Table 6. Summary of Reported Associations Between Pathophysiologic Mechanisms and Symptom Pattern in Functional
Dyspepsia
Mechanism
Associated symptoms
References
Delayed gastric emptying
Hypersensitivity to gastric distention
Impaired accommodation
H. pylori infection
Duodenal lipid hypersensitivity
Duodenal acid hypersensitivity
Unsuppressed phasic contractility
Atypical nonerosive reflux disease
Postprandial fullness, nausea, vomiting
Epigastric pain, belching, weight loss
Early satiety, weight loss
Epigastric pain
Nausea
Nausea
Bloating, absence of nausea
Epigastric pain
7, 11, 17, 36
9, 17
8, 10, 35, 36
14, 28, 56
66, 67, 68
71
79
111
Furthermore, induction of delayed gastric emptying in
healthy subjects by pharmacologic or dietary interventions
is not associated with the occurrence of dyspeptic symptoms.87 These observations question the relevance of delayed
emptying as a mechanism underlying dyspeptic symptoms.
Impaired Accommodation
A close correlation exists between impairment of
gastric accommodation, severity of early satiety, and the
amount of liquid meal ingested at maximum satiety
during a slow satiety drinking test.88 Erythromycin and
motilin induce a contraction of the proximal stomach.89,90 When these agonists are administered at the
time of meal ingestion, this results in impaired accommodation and is associated with early satiety.88,91 Relaxation of the proximal stomach can be activated by duodenal distention or nutrient infusion via a vagovagal
reflex pathway,92,93 and it requires activation of intrinsic
nitrergic neurons in the stomach.94 Administration of a
nitric oxide synthase inhibitor induces impaired accommodation in humans, and this is associated with early
satiety.95 These observations add further support to the
hypothesis that impaired accommodation is the mechanism underlying the symptom of early satiety.
Hypersensitivity to Gastric Distention
One study found an association between hypersensitivity to gastric distention, as determined by a gastric barostat study, and symptoms of pain and belching.9
However, this apparent association could be influenced
by a bias to report pain. In keeping with this possibility,
a significant association was found between symptoms of
pain, hypersensitivity to gastric distention, and several
psychopathologic mechanisms, including neuroticism,
somatization, a history of abuse, and health-related quality of life dimensions. Attempts to induce hypersensitivity in healthy subjects using a nitric oxide synthase
inhibitor were not successful.95,96 Recent data showed
that the N-methyl-D-aspartate receptor antagonist dextromethorphan sensitized the stomach to distention in
the absence of an effect on gastric compliance.97 However, this drug is not very selective, and it is unclear
whether this constitutes a valid model of visceral hypersensitivity and whether pretreatment with an N-methylD-aspartate antagonist induces dyspepsia-like symptoms
after ingestion of a meal.
Other Mechanisms
Acute H. pylori infection induces dyspepsia-like
symptoms, but these are transient.98 Nausea induced by
vestibular stimulation is also associated with abnormalities
of gastric electrical rhythm, suggesting that this may be a
secondary phenomenon accompanying nausea rather than a
primary mechanism.99 These observations question the direct pathophysiologic relevance of H. pylori and gastric
electrical dysrhythmias.
In healthy subjects, duodenal acid infusion sensitizes the
proximal stomach and the duodenum to distention and is
able to induce dyspepsia-like symptoms.100,101 Administration of the cholinesterase inhibitor neostigmine before a
meal induces unsuppressed postprandial phasic contractions
in healthy subjects, and this is associated with increased
scores for several dyspeptic symptoms.102 These observations suggest that increased duodenal acid exposure and
unsuppressed postprandial phasic contractility of the proximal stomach are mechanisms potentially involved in the
pathogenesis of dyspeptic symptoms. Table 6 summarizes
the reported associations between symptom patterns and
pathophysiologic mechanisms in functional dyspepsia.
Pathogenesis
The pathogenesis of functional dyspepsia is obscure, but a postinfectious or inflammatory origin has
been suggested for irritable bowel syndrome.103 Moreover, gastroparesis has been reported after a viral infection.104 Using a questionnaire in 400 consecutive patients with functional dyspepsia, we found that 17% had
a history with acute onset, suggestive of a postinfectious
origin.10 These patients had a particularly high preva-
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TACK ET AL.
lence of impaired accommodation. Because the proximal
stomach in these patients relaxed to administration of a
nitric oxide donor but did not respond to sumatriptan,
which releases nitric oxide through activation of 5-hydroxytryptamine (5-HT)1 receptors on nitrergic neurones, the abnormality is attributable to a dysfunction at
the level of gastric nitrergic neurons.10
As previously mentioned, whether psychological factors have a pathogenetic role in functional dyspepsia,
especially in patients with hypersensitivity to gastric
distention, or whether they are disease modulators determining health care seeking, perception of symptoms,
and the outcome of the disorder is not known. There are
several sources of evidence for a role of the central nervous system in visceral hypersensitivity. Studies in experimental animals indicate that acute psychological
stress facilitates increased sensitivity to visceral stimuli.105 In line with such a finding, rats genetically predisposed to anxiety have been shown to display an increased visceral sensitivity.106 Similarly, in humans, the
perception of gut distention has been found to be reduced during periods of distraction and increased during
periods of attentiveness or during mental stress associated with anxiety.107 However, the role of central factors
and stress in visceral hypersensitivity and symptom generation in functional dyspepsia remains to be established.
Finally, an association between dyspeptic symptoms
and a functional polymorphism in a G-protein subunit
was reported.108 It remains to be established whether this
genotype is associated with any specific pathophysiologic
mechanism, the likelihood of postinfectious functional
disorders, or altered psychosocial features.
Clinical Presentation and Diagnosis
Patients with predominant heartburn or acid regurgitation should, according to the Rome II criteria,
not be included in the dyspeptic spectrum but should be
referred to as having gastroesophageal reflux disease because the management differs substantially.5 It has been
proposed that a substantial number of patients with
predominant discomfort or pain centered in the upper
abdomen actually have atypical reflux disease.109 However, by using a simple questionnaire to screen for reflux
symptoms,110 only a minority of patients with predominant dyspeptic symptoms have pathologic reflux as
shown by 24-hour pH measurement.111 The use of these
questionnaires in clinical practice may prove useful to
detect patients who actually have reflux disease, with a
higher likelihood of being responders to treatment with
proton pump inhibitors (PPIs).
There is also a huge overlap between functional dyspepsia
and irritable bowel syndrome.2 For instance, in a referral
center, 46% of patients with functional dyspepsia proved to
have concomitant irritable bowel syndrome, and these patients were more likely to be female, have gastric hypersensitivity, and have more severe symptoms in general.112
Furthermore, many subjects change from predominant dyspeptic symptoms to bowel-related symptoms, indicating
irritable bowel syndrome, or the opposite during a 1-year
follow-up period.2
When a patient presents with dyspeptic symptoms, careful clinical evaluation and history taking are essential features to make a correct diagnosis of dyspepsia and to distinguish it from gastroesophageal reflux disease and irritable
bowel syndrome. Routine biochemistry is usually included
in the diagnostic workup, but the clinical value of this has
not been formally validated. So-called alarm symptoms
(prominent weight loss, recurrent vomiting, bleeding, anemia, dysphagia, jaundice, palpable mass) should be looked
for with great care and, if present, require additional diagnostic investigation. If there are no sinister symptoms and
the patient is young (younger than 45–50 years) and does
not take nonsteroidal anti-inflammatory drugs, upper endoscopy is rarely needed in the first line. However, early
endoscopy is of course the gold standard in the diagnostic
workup of dyspeptic patients with more severe symptoms
and may be associated with greater patient satisfaction,113
but it is not possible to perform this procedure in all
patients because of financial, practical, and patient-related
factors and other factors such as availability. Instead, other
strategies can be considered, namely initial empirical therapy114 –116 or a “test and treat” approach.54
The American Gastroenterological Association presented a medical position statement regarding the evaluation of dyspepsia in 1998 and recommended the “test
and treat” strategy,117 meaning initial testing for the
presence of H. pylori infection and, if present, eradication
therapy. H. pylori–negative patients should be offered
empirical antisecretory or prokinetic therapy. Based on
the existing studies on the effect of H. pylori eradication
on functional dyspepsia,55 it can be assumed that most
patients will still be symptomatic after treatment of H.
pylori and should in that case be offered endoscopy. These
guidelines were recently questioned by Spiegel et al.,
who by using a so-called decision analysis found empirical PPI therapy to be more cost effective, either as a first
step or following a “test and treat” approach, when the
patient has not responded favorably to eradication therapy.118 Moreover, these decision analyses cannot be extrapolated to every country because of major differences
in the prevalence of H. pylori infection, prevalence of
ulcers, accessibility of endoscopy, and cost of endoscopy.
October 2004
1247
Psychological symptoms are also common in patients
with functional dyspepsia as compared with patients
with organic causes of dyspepsia, such as duodenal ulcer.83 This may be more related to being a patient
seeking health care for dyspepsia than related to dyspepsia per se. A review found several psychosocial factors
such as life event stress, psychological morbidity, personality, abuse history, and abnormal illness behavior
and beliefs to be important factors in the process that
determines who will seek medical attention.120 The presence of psychosocial factors in these patients should be
addressed carefully but should not be overemphasized
because a causal role has not been established so far.
Treatment
General Measures
Figure 3. A clinical management algorithm based on currently available management guidelines and clinical experience.
A head-to-head comparison of these strategies is needed,
but in the meantime both strategies may be used and
have support in the literature. Although often used in
clinical practice, the empirical prokinetic therapy has
been less well studied. An in-depth analysis of clinical
management steps in dyspepsia was recently published in
GASTROENTEROLOGY.119 In general practice, the initial
empirical therapy is probably still the most widely used
approach. A clinical management algorithm based on
currently available management guidelines and clinical
experience is summarized in Figure 3.
Other investigations that might be considered in the
workup are, for instance, upper abdominal ultrasonography or computed tomography, small bowel radiography,
duodenal biopsy to exclude celiac disease, 24-hour esophageal pH monitoring, and manometric studies of the
upper gastrointestinal tract. These investigations should
not be performed in all patients but instead should be
based on the clinical picture, severity of symptoms, and
refractoriness of the patient.
Reassurance and education is of primary importance in patients with functional dyspepsia. It has been
shown in irritable bowel syndrome that a positive physician-patient interaction can reduce health care seeking,
and these findings are probably also valid for functional
dyspepsia.121 Lifestyle and dietary measures are usually
prescribed, although they have not been systematically
studied. It seems logical to have patients eat more frequent, smaller meals and desirable to avoid food that
aggravates symptoms. Because the presence of lipids in
the duodenum enhances the mechanosensitivity of the
stomach, avoiding meals with a high fat content might
be advisable.67,68 Coffee and spicy foods containing capsaicin are usually discouraged, although there is no evidence to link these food components to symptoms.122,123
In some patients, pharmacologic therapy will be considered. The pharmacologic treatments available to date
for the management of functional dyspepsia have only
been shown to be of limited efficacy. It seems logical that
directing therapeutic approaches toward the underlying
pathophysiologic disturbances should increase the efficacy,124 but this has not been proven.
Acid-Suppressive Drugs
In patients with gastroesophageal reflux, a trial of
antisecretory therapy has both therapeutic and diagnostic
value. Several studies have evaluated the use of H2receptor antagonists in functional dyspepsia, and a recent
meta-analysis showed superiority over placebo in improvement of pain but not for overall symptom improvement.125 PPIs have proven to be more effective than
H2-receptor antagonists and antacid-alginate in relieving
symptoms of uninvestigated dyspepsia (comparable to
the initial empirical PPI treatment previously mentioned).114 –116 Of course, these studies not only included
1248
TACK ET AL.
patients with functional dyspepsia but also patients with
peptic ulcer disease and with gastroesophageal reflux
disease. Large and well-controlled studies in functional
dyspepsia have shown that treatment with omeprazole
was approximately 10%–15% better than placebo in
patients with functional dyspepsia.15 However, this positive effect was restricted to patients with reflux-like
dyspepsia, a subgroup that actually is no longer considered to belong to functional dyspepsia, and to a lesser
degree in patients with ulcer-like dyspepsia. In patients
with dysmotility-like dyspepsia, no effect could be observed.15
In a recent study in consecutive patients with functional
dyspepsia without dominant symptoms of heartburn,
pathologic esophageal acid exposure was present in a subset
of patients who were characterized by a higher prevalence of
epigastric pain.111 This finding suggests that patients with
ulcer-like dyspepsia who respond to acid-suppressive therapy may actually have gastroesophageal reflux disease. On
the other hand, recent studies have suggested a role for
increased duodenal acid exposure and duodenal acid hypersensitivity in the pathogenesis of functional dyspepsia.71,72
Treatment with PPIs tended to decrease duodenal acid
hypersensitivity, but so far no symptomatic benefit in this
group of patients has been shown.126
Prokinetic Agents
Prokinetic agents, including metoclopramide, domperidone, and cisapride, are widely used in functional dyspepsia. The rationale is to use prokinetic drugs in patients
with delayed gastric emptying, in which they should improve symptoms of postprandial fullness, nausea, and vomiting. However, studies available so far fail to prove this
hypothesis, and evidence that the symptomatic improvement is related to enhancement of gastric emptying is
lacking.127–130
Metoclopramide and domperidone are dopamine receptor agonists with a stimulatory effect on upper gastrointestinal motility. Unlike metoclopramide, domperidone does
not cross the blood-brain barrier. Cisapride facilitates the
release of acetylcholine in the myenteric plexus via 5-HT4
receptor agonism and accelerates gastric emptying.127–130
The availability of cisapride is restricted due to cardiac
safety issues. Recently, tegaserod, a partial 5-HT4 agonist,
was found to accelerate gastric emptying, indicating its
possibility as a prokinetic agent.131
Recent reviews suggest that prokinetics, especially domperidone and cisapride, are more effective than placebo, but
the trials were often of poor quality with significant heterogeneity between studies.127–130 However, the gastroprokinetic effects of these drugs are limited, and the finding of
the strong gastrokinetic actions of erythromycin, a macro-
lide antibiotic that acts as a motilin receptor agonist, was
met with great enthusiasm.132 Several short-term studies
reported beneficial effects of treatment with erythromycin
in gastroparesis.132–134 Different macrolide prokinetics, devoid of antibiotic properties, were developed and one of
these, ABT-229, was studied in large clinical trials.135
However, the outcomes of clinical trials with ABT-229
were unequivocally disappointing with regard to symptom
improvement, both in dyspeptic patients with and without
delayed emptying. It has been argued that the negative
outcomes of the studies with ABT-229 show that acceleration of gastric emptying is not the correct therapeutic
target in functional dyspepsia,135 but there are also strong
indications of tachyphylaxis with macrolide prokinetics.136,137 Furthermore, it is well established that erythromycin and related compounds impair gastric accommodation to a meal,89 –91 thereby enhancing sensitivity to gastric
distention,48 which may have contributed to the overall
poor symptomatic effect. Cisapride and tegaserod were
shown to enhance gastric accommodation to a meal138,139
and are therefore less likely to worsen or induce symptoms
related to impaired accommodation. In addition, in preliminary studies, we showed a tendency for tegaserod to improve upper gastrointestinal symptoms in female patients
with functional dyspepsia with normal gastric emptying,
suggesting that it may affect pathophysiologic mechanisms
other than delayed gastric emptying.140
Eradication of H. pylori
The 4 largest published randomized trials on the
effect of H. pylori eradication on symptoms in functional
dyspepsia show somewhat conflicting results. A singlecenter trial suggested a small superiority of eradication
treatment versus PPI treatment alone,141 but 3 multicenter
trials had negative findings.142–144 Taken together, these 4
large studies suggest that the potential symptomatic benefit
of H. pylori treatment in functional dyspepsia is probably of
limited importance. Other arguments in favor of the use of
eradication therapy are protection against peptic ulcer, putative protection against gastric cancer, and the short-term
nature of the treatment.145
Antidepressants
There is some evidence that tricyclic antidepressants are effective in treating patients with functional
gastrointestinal disorders, including functional dyspepsia.146,147 Generally, lower doses are used than for treatment of depression. Mianserin, at a high dose, was also
shown to be superior to placebo in patients with functional gastrointestinal disorders, including dyspepsia.148
The mechanism behind the positive effect has been proposed to be due to an effect on gastric sensitivity, but
October 2004
this could not be confirmed in the study by Mertz et
al.147 In clinical practice, it seems that the positive effect
is not clearly related to the presence or absence of depression. It is unclear whether selective serotonin reuptake inhibitors (SSRIs) are also effective treatment
alternatives for functional gastrointestinal disorders.
These drugs increase the availability of synaptically released 5-HT not only in the central nervous system but
also at the level of the enteric nervous system. Pretreatment with the SSRI paroxetine strongly enhanced the
meal-induced relaxation of the proximal stomach in
healthy subjects.149 This observation suggests involvement of 5-HT in the gastric accommodation reflex in
humans as well as a potential beneficial effect of SSRIs in
dyspeptic patients with impaired accommodation. In an
open-label study in dyspeptic patients with abnormalities on electrogastrography, only patients with coexisting
depression improved and gastric myoelectrical activity
did not improve.150
Fundus-Relaxing Drugs
It seems logical that restoring gastric accommodation in patients with impaired accommodation is
likely to improve symptoms of early satiety. Short-term
studies have shown some benefit of nitrates,151 but prolonged use is generally associated with undesirable vascular side effects due to the lack of specificity. Sildenafil
blocks phosphodiesterase type 5, which degrades nitric
oxide–stimulated guanosine 3=,5=-cyclic monophosphate, thereby relaxing smooth muscle in various organs.
Pretreatment with sildenafil also relaxes the proximal
stomach,152 and trials evaluating phosphodiesterase inhibitors in functional dyspepsia seem warranted. Similar
to the central nervous system, serotonin reuptake in the
enteric nervous system is also inhibited by SSRIs.153 The
enhancement of gastric accommodation by pretreatment
with the SSRI paroxetine suggests involvement of 5-HT
in the control of the accommodation reflex in humans.149
The 5-HT receptor involved has not been identified, but
both 5-HT1 and 5-HT4 receptors can mediate enhanced
postprandial gastric relaxation. Pretreatment with the
5-HT4 receptor agonists cisapride and tegaserod enhances gastric accommodation in healthy subjects.138,139
Administration of sumatriptan, a 5-HT1 receptor agonist
used in the treatment of migraine, relaxes the proximal
stomach in healthy subjects.154 In short-term studies,
subcutaneous administration of sumatriptan was shown
to restore meal-induced relaxation in patients with impaired gastric accommodation and to increase the
amount of calories ingested at maximum satiety in patients with early satiety.8 Due to its pharmacologic properties, cost, and mode of administration, subcutaneous
1249
sumatriptan is not suitable for long-term treatment of
functional dyspepsia. A nasal-spray formulation of
sumatriptan had no significant effect on proximal stomach function.155 Buspirone is a nonselective 5-HT1 receptor agonist used in the treatment of panic attacks. In
a placebo-controlled study in patients with functional
dyspepsia, we confirmed that buspirone was superior to
placebo in alleviating dyspeptic symptoms and that this
was associated with an enhancement of the accommodation to a meal.156 Clonidine, an ␣2 receptor agonist, also
relaxes the stomach and reduces gastric sensation.157
Short-term administration of clonidine was found to
decrease meal-induced symptoms in functional dyspepsia.50
Other Drugs
Dose-finding studies with the 5-HT3 receptor
antagonist alosetron showed potential benefit in functional dyspepsia.158 The mechanisms behind its effect
are at present unclear. No effect on gastric sensitivity
in healthy volunteers has been shown,159 but 5-HT3
receptor antagonism reduces duodenal lipid sensitivity.63 Alosetron was on the U.S. market for approximately 6 months for diarrhea-predominant irritable
bowel syndrome, but its use is now restricted due to
safety issues.160
Cholecystokinin receptor antagonists also reduce duodenal lipid sensitivity and are currently under evaluation.64,66
The ␬ opioid agonist fedotozine decreases gastric sensitivity
to distentions,161 and it showed superiority over placebo in
a placebo-controlled study in patients with functional dyspepsia.162 However, development of this drug has not continued. Asimadoline, another ␬ opioid agonist that was
shown to decrease satiation and meal-induced fullness,163 is
currently still under evaluation.
A recent study showed that long-term administration of red pepper was more effective than placebo in
decreasing the intensity of dyspeptic symptoms in
patients with functional dyspepsia.123 Such a contradictory result might be explained by the finding that
capsaicin initially produces sensitization but repeated
stimulation of the capsaicin receptor on capsaicinsensitive primary afferents leads to desensitization.164
Studies of the effect of capsaicin on gastric sensitivity
in humans, which showed acute sensitization followed
by decreased perception of epigastric symptoms,165 are
in keeping with this mechanism of action. In a controlled trial in patients with functional dyspepsia,
artichoke leaf extract was significantly better than
placebo in alleviating symptoms and in improving
quality of life.166 The basis for this improvement
remains to be identified.
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TACK ET AL.
Psychological Interventions
Psychological factors are considered important
contributors to symptom severity in patients with functional gastrointestinal disorders, including functional
dyspepsia.8,167 This suggests that psychological treatment alternatives might be useful in these patients.
A review of clinical trials of psychological interventions for functional dyspepsia showed potential benefits in the treatment of functional dyspepsia.168 However, several studies did not control for additional
time and attention the patients received in the psychological intervention arms, making it difficult to
exclude a contribution of nonspecific factors. Another
study controlled for this factor compared psychodynamic-interpersonal psychotherapy with supportive
therapy in 95 consecutive patients with functional
dyspepsia who had failed to respond to conventional
pharmacologic treatments.169 At the end of treatment,
patients receiving psychotherapy had a significantly
better outcome than those receiving supportive therapy. One year after treatment, the symptom scores
were similar in both groups, but a post hoc analysis
excluding patients with severe heartburn also showed
a positive effect of psychotherapy at 1 year. Hypnotherapy was also shown to be useful in functional
dyspepsia in a randomized study compared with supportive or medical therapy.170 In a follow-up of 1 year,
the effect was maintained. Hence, assessing psychosocial issues and intervening at this level in patients
with functional dyspepsia seems to be a reasonable
approach. However, in clinical practice, this approach
is usually reserved for those with severe and extensive
symptomatology or refractory disease.
Conclusions
Functional dyspepsia is one of the most common disorders seen in general practice and by gastroenterologists. Functional dyspepsia seems to be a
heterogenous disorder in which different pathophysiologic disturbances are associated with different
symptom profiles. The available options for the treatment of functional dyspepsia are of limited efficacy,
which probably reflects the incomplete understanding of the nature of this disorder. Current knowledge
is in support of empirical treatment with acid-suppressive agents and prokinetics as well as identification and treatment of H. pylori infection. Refractory
patients may benefit from treatment with antidepressants or psychological interventions. More effective
approaches are badly needed, and this will probably
require ongoing efforts to elucidate underlying pathophysiology.
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Received November 20, 2003. Accepted May 6, 2004.
Address requests for reprints to: Jan Tack, M.D., Ph.D., Division of
Gastroenterology, Department of Internal Medicine, University Hospital
Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. e-mail:
jan.tack@med.kuleuven.ac.be; fax: (32) 16-34-44-19.

SPECIAL REPORTS AND REVIEWS Pathophysiology and Treatment of Functional Dyspepsia

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