Organic Versus Functional: Dyspepsia

CLINICAL REVIEW
Dyspepsia
Organic Versus Functional
Pantelis Oustamanolakis, MD*w and Jan Tack, MD, PhD*w
ranging from pain or discomfort to postprandial fullness,

Abstract: Dyspepsia is the medical term for difficult digestion. It early satiation, abdominal bloating, belching, or even
consists of various symptoms in the upper abdomen, such as full- sometimes nausea and vomiting.1,2 Patients usually present
ness, discomfort, early satiation, bloating, heartburn, belching, with several of these symptoms, leading to a variety of
nausea, vomiting, or pain. The prevalence of dyspepsia in
the western world is approximately 20% to 25%. Dyspepsia can
clinical presentations of dyspepsia, thus making it one of
be divided into 2 main categories: “organic” and “functional the most common problems in everyday clinical practice.3
dyspepsia” (FD). Organic causes of dyspepsia are peptic ulcer, The severity and intensity of symptoms also vary from very
gastroesophageal reflux disease, gastric or esophageal cancer, mild symptoms in patients who do not seek medical
pancreatic or biliary disorders, intolerance to food or drugs, and attention to very severe ones that may lead to sitophobia
other infectious or systemic diseases. Pathophysiological mecha- (fear to eat), anorexia, and weight loss. Historically, the
nisms underlying FD are delayed gastric emptying, impaired gastric Rome I and II consensus defined dyspepsia as “pain or
accommodation to a meal, hypersensitivity to gastric distension, discomfort in the upper abdomen,”1,2 with “discomfort”
altered duodenal sensitivity to lipids or acids, altered an- including postprandial fullness, upper abdominal bloating,
troduodenojenunal motility and gastric electrical rhythm, unsup-
pressed postprandial phasic contractility in the proximal stomach,
early satiety, epigastric burning, belching, nausea, and
and autonomic nervous system-central nervous system dysregula- vomiting. After the Rome III consensus, dyspepsia has been
tion. Pathogenetic factors in FD are genetic predisposition, in- restricted to symptoms that are typically arising from the
fection from Helicobacter pylori or other organisms, inflammation, gastroduodenal region, maintaining only 4 cardinal symp-
and psychosocial factors. Diagnostic evaluation of dyspepsia in- toms (postprandial fullness, early satiation, epigastric pain,
cludes upper gastrointestinal endoscopy, abdominal ultrasonography, and epigastric burning), although many other symptoms
gastric emptying testing (scintigraphy, breath test, ultrasonography, may coexist in dyspeptic patients.4 Heartburn, as the pre-
or magnetic resonance imaging), and gastric accommodation eval- dominant symptom, has been considered to characterize
uation (magnetic resonance imaging, ultrasound, single-photon patients with gastroesophageal reflux disease (GERD) and
emission computed tomography, and barostat). Antroduodenal
not dyspepsia, although overlap with dyspepsia is common.
manometry can be used for the assessment of the myoelectrical
activity of the stomach, whereas sensory function can be evaluated Dyspepsia can be divided into 2 main categories:
with the barostat, tensostat, and satiety test. Management of FD “organic” when the clinical and laboratory investigation
includes general measures, acid-suppressive drugs, eradication may identify an underlying organic disease that is likely to
of H. pylori, prokinetic agents, fundus-relaxing drugs, anti- be the cause of the symptoms and “functional dyspepsia”
depressants, and psychological interventions. This review presents (FD) when no organic abnormality is identified by the di-
an update on the diagnosis of patients presenting with dyspepsia, agnostic workup, including gastroscopy and when no ob-
with an emphasis on the pathophysiological and pathogenetic vious specific cause of the symptoms has been found.
mechanisms of FD and the differential diagnosis with organic Diagnostic overlap with GERD and irritable bowel syn-
causes of dyspepsia. The management of uninvestigated and FD,
drome (IBS) is very frequent, but it does not exclude a
as well as the established and new pharmaceutical agents, is also
discussed. diagnosis of FD.
This review presents an update on the diagnostic
Key Words: organic dyspepsia, functional dyspepsia, dyspepsia, approach to patients presenting with dyspepsia, with an
functional gastrointestinal disorders emphasis on the pathophysiological and pathogenetic
mechanisms underlying FD and the management of unin-
(J Clin Gastroenterol 2012;46:175–190)
vestigated and FD.
D yspepsia is the medical term used to describe the sense

of “difficult digestion.” The term refers to a very hetero-
genous group of symptoms, located in the upper abdomen,
EPIDEMIOLOGY
Dyspeptic symptoms are very common in general
population, with prevalence estimates ranging between
10% and 45%.5–11 The results of prevalence studies are
From the *Department of Pathophysiology, Translational Research strongly influenced by criteria used to define dyspepsia, and
Center for Gastrointestinal Disorders (TARGID), University of in line with recent consensus definitions, it is essential that
Leuven; and wDepartment of Gastroenterology, University Hospi- patients with predominant heartburn should be excluded,
tal Gasthuisberg, Leuven, Belgium.
P.O. has received a scholarship research grant from the Hellenic Society
but this was not done in many of the studies. When
of Gastroenterology. Jan Tack has nothing to declare. heartburn is excluded, the prevalence of uninvestigated
The authors declare that they have nothing to disclose. dyspepsia in the general population is in the range of 5% to
Reprints: Jan Tack, MD, PhD, Department of Pathophysiology, 15%.6,7,10,11 Well-performed epidemiological studies have
Translational Research Center for Gastrointestinal Disorders
(TARGID), University of Leuven, B-3000 Leuven, Belgium (e-mail:
reported a prevalence of approximately 20% to 25% in
[email protected]). the western world,8,12,13 slightly higher in women, with a
Copyright r 2012 by Lippincott Williams & Wilkins variable influence of age across studies. The majority of
J Clin Gastroenterol Volume 46, Number 3, March 2012 www.jcge.com | 175

Oustamanolakis and Tack J Clin Gastroenterol Volume 46, Number 3, March 2012
these patients have no identifiable cause by standard diag- gastric or esophageal cancer, and a major finding was that
nostic tests.14 The annual incidence rate of dyspepsia has age or the presence of “alarm” symptoms did not effectively
been estimated to range between 1% and 6%.6 Long-term predict endoscopic findings.27 These data were also con-
follow-up studies suggest improvement or symptom reso- firmed later by 3 big studies,24,28,29 suggesting that the
lution in approximately half of the patients.6,9 “decision for endoscopy” threshold of the clinician should be
Quality of life is significantly affected in dyspepsia, lower than the guidelines based on age or alarm symptoms.
especially FD.15 Despite the fact that only about 1 in 4 with
dyspeptic symptoms chooses to consult a physician,13,16 Pancreatic or Biliary Tract Disorders
dyspepsia is a clinical problem of considerable cost for the Despite the high prevalence of both dyspepsia and
health care system because of the high prevalence and the gallstones in adults, epidemiological studies have confirmed
chronic or recurrent nature of symptoms.17,18 Factors in- that cholelithisis is not associated with dyspepsia. There-
fluencing health care seeking are symptom severity, fear of fore, patients with dyspepsia should not be investigated
underlying serious disease, psychological distress, and lack routinely for cholelithiasis, and cholecystectomy for chol-
of adequate psychosocial support.19 elithiasis is not indicated for dyspepsia alone. The clinical
presentation of biliary colic is easily distinguishable from
ORGANIC CAUSES OF DYSPEPSIA that of dyspepsia. Whether sphincter of Oddi dysfunction
The most important identifiable organic causes of may contribute to dyspeptic symptom generation is unclear.
dyspeptic symptoms are peptic ulcer disease and GERD. Pancreatic disease is less prevalent, but symptoms of
Malignancies of the upper gastrointestinal (GI) tract and pancreatitis (acute or chronic) or pancreatic cancer may
celiac disease are less common but clinically relevant causes initially be mistaken for dyspepsia. However, pancreatic
of dyspeptic symptoms.20–24 The investigation of choice disorders are usually associated with more severe pain and
for dyspeptic symptoms is endoscopy, which may identify are often accompanied by anorexia, rapid weight loss,
erosive esophagitis, peptic ulcer, or gastric or esophageal jaundice, or other symptoms of pancreatic insufficiency, for
cancer. example steatorrhoea and possibly diabetes mellitus.
Peptic Ulcer Intolerance to Food or Drugs

Peptic ulcer is a well-established cause of dyspeptic Contrary to popular beliefs, ingestion of specific foods
symptoms and is an important management consideration. such as spices, coffee, or alcohol, or excessive amounts of
However, the prevalence of peptic ulcer in dyspeptic sub- food, has never been established to cause dyspepsia.5,30
jects is only 5% to 10%.20,24,25 Chronic peptic ulcer, in Although food ingestion often aggravates dyspeptic symp-
most cases, is caused by H. pylori infection or nonsteroidal toms, this is probably more related to the sensorimotor
anti-inflammatory drugs (NSAIDs). Typically, a history of response to food and usually does not involve specific in-
prompt and good symptomatic relief by a course of H2- tolerances or allergies. Recent studies have shown that
receptor antagonists (H2RA) or proton-pump inhibitors acute ingestion of capsaicin induces dyspeptic symptoms in
(PPIs) suggests an acid-related disorder (either peptic ulcer health and in FD, with increased intensity in the latter
or reflux). Unfortunately, classical ulcer-type symptoms do group.31
not adequately discriminate peptic ulcer disease from FD. Dyspepsia is a common side effect of many drugs,
including iron, antibiotics, narcotics, digitalis, estrogens
GERD and oral contraceptives, theophylline, levodopa, and many
Erosive esophagitis is a diagnostic marker for GERD, others. NSAIDs have received most attention because of
but many GERD patients have no endoscopic signs of their potential to induce ulceration in the GI tract. Chronic
esophageal erosion, and this is referred to as nonerosive use of aspirin and other NSAIDs may provoke dyspeptic
reflux disease. Erosive esophagitis is found in approx- symptoms in up to 20% of subjects, but the occurrence of
imately 20% of dyspeptic patients, and a similar number of dyspepsia correlates poorly with the presence of ulcers. In
patients may have nonerosive reflux disease.20,24 In a recent controlled trials, 4% to 8% of persons treated with
meta-analysis of the prevalence of clinically significant en- NSAIDs develop dyspepsia, with odds ratios ranging from
doscopic findings in 5389 subjects with dyspepsia, erosive 1.1 to 3.1 compared with placebo, and the magnitude of this
esophagitis was the most common abnormality (pooled effect depends on the dose and type of NSAID.25 Com-
prevalence, 13.4%), followed by peptic ulcer (pooled pared with NSAIDs, cyclooxygenase-2 selective inhibitors
prevalence, 8.0%). The prevalence of erosive esophagitis are associated with a lower frequency of dyspepsia and
was lower when Rome criteria were used to define dyspeptic ulceration.32
pepsia compared with a broad definition (6% vs. 20%).26
Other GI or Systemic Disorders
Gastric or Esophageal Cancer Several GI disorders may cause dyspepsia-like symp-
The risk of gastric or esophageal malignancy in pa- toms. These include infectious (the parasites Giardia lamblia
tients with dyspeptic symptoms is estimated to be < 1%.23 and Strongyloides stercoralis, tuberculosis), inflammatory
The risk of gastric cancer is increased among patients with (celiac sprue, Crohn’s disease, sarcoidosis, lymphocytic
H. pylori infection, patients with a family history of gastric gastritis, and eosinophilic gastroenteritis), or infiltrative
malignancy, patients with a previous history of gastric (lymphoma, amyloid, and Ménétrier disease) disorders of
surgery, or immigrants from endemic areas. The risk for the upper GI tract. Most of these will be identifiable at
esophageal cancer is increased in males, smokers, subjects upper GI endoscopy with biopsies. Recurrent gastric vol-
with a high consumption of alcohol, and with a long- vulus and chronic mesenteric or gastric ischemia may also
standing history of heartburn. In a multicenter database present with dyspeptic symptoms.
study with 3815 patients with dyspeptic symptoms who The symptom pattern associated with gastroparesis
underwent upper GI endoscopy, 2% were found to have (idiopathic, drug-induced or secondary to metabolic, sys-
176 | www.jcge.com r 2012 Lippincott Williams & Wilkins

J Clin Gastroenterol Volume 46, Number 3, March 2012 Dyspepsia
temic, or neurological disorders) is very similar to dyspep- patients.33 However, in the largest studies, gastric emptying
sia, and the distinction between idiopathic gastroparesis of solids was delayed in about 30% of patients.3,4,34–36
and FD with delayed gastric emptying is not well defined. Most studies failed to find a convincing relationship between
Idiopathic gastroparesis could be considered a candidate delayed emptying and symptom pattern, although large-scale
mechanism contributing to unexplained upper GI symptoms single-center studies from Europe showed that patients with
(FD), rather than a separate “disease entity,” “disorder,” or delayed gastric emptying for solids were more likely to report
“syndrome.” postprandial fullness, nausea, and vomiting.34–38
Whether delayed gastric emptying causes symptoms,
PATHOPHYSIOLOGICAL MECHANISMS IN FD or is an epiphenomenon, is a matter of ongoing con-
troversy. It has been suggested that larger intragastric
In health, the major motor functions of the stomach
volume and, hence, increased distension as a result of de-
are to temporarily store ingested food during the process of
layed gastric emptying is responsible for increased feelings
breakdown of solids, to empty chyme appropriately into
of satiety and delayed return of hunger.39,40 In contrast,
the small bowel, and to empty indigestible solids remaining
there are studies in the literature that favor rapid, rather
in the stomach after a meal (Fig. 1). During ingestion of a
than delayed, gastric emptying, as a possible cause of FD
meal, vagally mediated receptive relaxation of the proximal
symptoms.41
stomach occurs in response to swallowing. This relaxation
prepares the proximal stomach to receive esophageal con- Impaired Gastric Accommodation to a Meal
tents and is followed by gastric accommodation, whereby
The proximal stomach serves mainly as a reservoir
the proximal stomach progressively relaxes to store in-
during and after ingestion of the meal.42 This accom-
creasing food volumes while maintaining a low intragastric
modation process consists of a receptive relaxation induced
pressure. Solid emptying is largely controlled by antral and
by swallowing and bolus passage through the esophagus
pyloric motor activity. Phasic contractions sweep from the
and an adaptive relaxation elicited by mechanical dis-
midstomach to the pylorus, at a frequency of 3/min, mixing
tension of the stomach and chemical stimulation in the
and grinding the food until particles are approximately
duodenum. The fasting tone of the proximal stomach is
1 mm in size. Emptying of liquids is controlled by coordi-
maintained by the balance of vagally mediated cholinergic
nated motor activity of the entire stomach and is driven by
input and continuous nitrergic input.43,44 Studies on ani-
proximal gastric tone. The pylorus is an important func-
mals have demonstrated that the gastric accommodation to
tional component of the gastroduodenal region and also
a meal is mediated by a vagovagal reflex pathway, involving
regulates solid and liquid emptying, based on duodenal
nonadrenergic and noncholinergic pathways.45,46 Recently,
feedback concerning the osmolality and fat content of the
it was shown that the accommodation reflex in humans
meal, the amount of gastric acid secreted, and duodenal
lacks a cephalic phase, but it can be activated from the
motility.
oropharynx, the stomach, and the duodenum.47
Delayed (or Rapid) Gastric Emptying Studies using the gastric barostat, scintigraphy, ultra-
sonography, single-photon emission computed tomo-
Several studies have investigated gastric emptying and
graphy, or noninvasive surrogate markers (satiation drinking
its relationship to symptom pattern and severity in FD. The
test) have all shown the presence of impaired accommodation
prevalence of delayed gastric emptying ranges from 20% to
in approximately 40% of FD patients.3,4,42,48,49 Although a
50%.3,4 In a meta-analysis of 17 studies involving 868
number of studies found associations of impaired accom-
dyspeptic patients and 397 controls, significant delay of
modation with early satiation and weight loss, others failed to
solid gastric emptying was present in almost 40% of FD
find such association.3,4,42,48,50,51
The mechanisms through which impaired accom-
modation can contribute to symptom generation are still
unclear, but insufficient relaxation of the proximal stomach
during and after the ingestion of a meal may cause in-
creased intragastric pressure and activation of tension-
sensitive mechanoreceptors in the gastric wall.42 Increased
gastric wall tension may induce symptoms, and increased
intragastric pressure may be associated with increased
postcibal perception and satiation.39,52,53 In contrast, in-
sufficient accommodation of the proximal stomach may
force the meal into the distal stomach, thereby causing
activation of tension-sensitive mechanoreceptors in a dis-
tending antrum.42
The cause of impaired accommodation in FD has not
been established. In theory, impaired accommodation can
result from a disorder at the level of the sensory apparatus,
the vagovagal reflex pathway, the intrinsic inhibitory in-
nervation, or the smooth muscle in the proximal stomach.
Impaired accommodation is more prevalent in patients
FIGURE 1. Normal fasting and postprandial gastric function: with acute onset, presumably postinfective FD, where it is
schematic presentation of pathogenetic factors, pathophysio- attributable to impaired nitrergic nerve function in the
logical mechanisms, and symptoms involved in functional dys- stomach.49 In contrast, psychological factors, mainly
pepsia. ANS indicates autonomic nervous system; CNS, central anxiety, may also negatively affect the accommodation
nervous system. Arrow represent directions of influencing. reflex.54 Recently, it was shown that meal-induced gastric
r 2012 Lippincott Williams & Wilkins www.jcge.com | 177

accommodation was significantly inhibited by rimonabant, persensitivity and abuse history. These observations pro-
an endocannabinoid-1 receptor antagonist, suggesting vide evidence for central mechanisms of hypersensitivity
endocannabinoid involvement in the control of gastric contributing to symptom generation in FD.67 A possible
accommodation.55 role for psychosocial factors in the pathogenesis of visceral
hypersensitivity has been presented in some studies. In a
Hypersensitivity to Gastric Distension large cohort of FD patients, a history of abuse was asso-
Visceral hypersensitivity, defined as abnormally en- ciated with increased sensitivity to gastric distention,
hanced perception of visceral stimuli, is considered one whereas no association with gastric emptying rate was
of the major pathophysiological mechanisms underlying found.68 In another study of 201 consecutive FD patients,
functional GI disorders.56 Using the barostat device, sev- symptom severity and weight loss were mainly determined
eral investigators have demonstrated that FD patients as a by psychosocial factors such as depression, abuse history,
group have lower sensory thresholds to balloon distension and somatization and to a lesser extent by visceral hyper-
of the proximal stomach and the duodenum than healthy sensitivity. Motor dysfunction was not an independent
volunteers.57 A large-scale study found hypersensitivity to determinant of symptom severity in this cohort.69
gastric distension in 34% of FD patients.57 An interesting
finding is that hypersensitivity to gastric distensions seems Altered Duodenal Sensitivity to Lipids or Acids
to be related to functional dyspepsia, but not organic dys-
In health and in FD, duodenal perfusion with nutrient
pepsia,58 and is also found in dyspeptic subjects who are not
lipids, but not glucose, enhances the perception of gastric
health care seekers, implying that it is not solely an ex-
distention through a mechanism that requires lipid diges-
pression of referral bias or personality factors.59 The level at
tion and subsequent release of cholecystokinin (CCK).70–72
which visceral hypersensitivity is generated is unclear; there
Evidence in the literature indicate that in healthy subjects,
is, however, evidence for involvement of “in series” tension-
CCK-A receptors, and to a lesser extent 5-HT3 receptors,
sensitive mechanoreceptors and alterations at the level of the
mediate effects of duodenal lipid infusion on GI sensa-
central nervous system or of visceral afferents.60–62
tions.70,73 In addition, duodenal lipid infusion was shown to
Altered chemosensitivity of the GI tract is another
increase intestinal sensitivity by modulating intestinal me-
parameter that has only recently been introduced. Cap-
chanoreceptor response.74 Hydrolysis of fat by lipases with
saicin-sensitive afferent nerves have been implicated in the
activation of chemoreceptors by the lipolytic products
control of GI sensorimotor function, and it seems that
seems to be required for the modulation of GI sensations
upregulation of the capsaicin-sensitive transient receptor
during gastric distension. However, all of these studies used
potential V1 channel could be a mechanism of hyper-
intraduodenal mode administration and were not replicated
sensitivity.63 In FD, ingestion of a capsaicin capsule induces
with orally ingested lipid-containing meals.75,76
significantly more intense symptoms compared with
Duodenal infusion of hydrochloric acid-induced nau-
health.31 One of the endogenous ligands for the transient
sea in FD, but not in health, suggests duodenal hyper-
receptor potential V1 is acid, and gastric acid has been
sensitivity to acid.77 Duodenal pH monitoring, using a
implicated in mechanisms of sensitization in upper GI dis-
clipped pH electrode, revealed increased postprandial du-
orders, including FD. This was confirmed by a study64 in
odenal acid exposure in FD compared with controls, and
which esophageal acid perfusion in healthy controls (HCs)
this was attributable to impaired clearance of acid.78 In
sensitized the stomach to distention but not when perfused
another study, using wireless pH monitoring capsules
acid was aspirated just below the lower esophageal
clipped to the duodenum, FD patients showed significantly
sphincter. Enhanced chemosensitivity in FD is in agreement
lower pH values during meals and daytime, compared with
with the observation that an upregulation of multimodal
controls, but the correlation with symptoms was poor.79
sensory pathways is found in hypersensitive FD.62
Duodenal acid perfusion of 12 healthy subjects, during
The mechanisms underlying visceral hypersensitivity
fasting and postprandially, increased bloating, discomfort,
are not yet completely understood. One hypothesis is
epigastric pain, and nausea severity scores, arguing in favor
defective function of descending antinociceptive pathways
of its pathophysiological relevance.80
in the brain, which suppress discomfort or pain from
the viscera under physiological circumstances. Endogenous
opioids have been proposed as an important candidate Other Pathophysiological Mechanisms
mediator of endogenous antinociception, but admin- Upper GI manometry studies have established that
istration of naloxone, a nonselective opioid antagonist, had antral hypomotility is a common feature in FD.81 It is
no significant influence on gastric sensitivity but had de- unclear whether this reflects true hypomotility or a poor
creased gastric accommodation, suggesting that endoge- recording of contractions in a dilated antrum in patients
nous opioids are involved in gastric motor control rather with impaired accommodation, or both, as manometry only
than sensitivity.65 In a positron emission tomography study registers lumen-obliterating contractions. Small-bowel
of 25 FD patients and 11 controls during baseline, gastric motor alterations, usually hypermotility with burst activity
balloon, or sham distension, balloon distension was asso- or clusters, and an increased proportion of duodenal
ciated with a lack of pregenual anterior-cingulated cortex retrograde contractions have also been reported, but no
activation in patients only.66 Patients showed no dorsal clear correlation with symptoms has been found.82
pons and amygdala deactivation during distension and There is also evidence that abnormalities in the control
sham, respectively. Anxiety correlated negatively with pre- of gastric myoelectrical activity, as measured by cutaneous
genual anterior-cingulated and positively with dorsal pons electrogastrography, are present in a subset of FD pa-
activity. These data were evaluated as arousal-anxiety- tients,83–85 but no correlation was found between symptom
driven failure of pain modulation. In the same patient pattern and electrogastrogram.
group, brain activation patterns and symptom ratings Autonomic nervous system dysfunction has been re-
during balloon distension were influenced by gastric hy- ported in FD, including efferent vagal dysfunction,86,87

which has been implicated in impaired accommodation88 interleukin (IL)-5 and IL-13 production and decreased
and antral hypomotility.86 stimulated interferon-g and IL-10 production, were de-
A few studies, which have investigated the role of gut tected in FD, and some changes in immune function were
hormones in FD symptom generation,89 particularly asso- more pronounced in the PI-FD group.107 In a study from
ciated with fat ingestion, suggest that CCK, secreted from Germany and Australia with 45 H. Pylori-negative patients
the small intestine in response to the presence of products with FD and 35 HCs, it was shown that FD patients had
of fat and protein digestion,90 contributes to the patho- significantly higher tissue necrotic factor-a, IL-1b, and IL-
genesis of FD. There is evidence, albeit limited, that intra- 10 levels and enhanced gut homing lymphocytes compared
venous infusion of the CCK analog, CCK-8, induces with HC. Cytokine release and CD4+a4b7+CCR9+
symptoms in a much greater proportion of patients with FD lymphocytes were correlated with the symptom intensity of
than healthy volunteers,91 suggesting that the “sensitivity” to pain, cramps, nausea, and vomiting. Delayed gastric emp-
CCK may be increased. Moreover, fat-induced dyspeptic tying was significantly associated with CD4+a4b7+
symptoms have been reported to be attenuated, both acutely CCR9+ lymphocytes and IL-1b, tissue necrotic factor-a,
and chronically, by dexloxiglumide.91 Fasting and post- and IL-10 secretion.108 These observations are suggestive
prandial CCK concentrations are greater in FD and related to of ongoing duodenal and systemic immune activation in
the severity of nausea.92 PI-FD.
Contradicting results have been published on plasma Dizdar et al109 compared duodenal biopsies in patients
levels of glucagon-like peptide 1, peptide YY, ghrelin, and with persisting symptoms after treated Giardia infection
motilin. with those patients with complete symptom resolution after
the same treatment. Patients with persisting symptoms
PATHOGENETIC FACTORS IN FD had higher numbers of CCK cells but lower numbers of
enterochromaffin cells. Plasma CCK levels correlated sig-
Genetic Predisposition nificantly with dyspepsia scores, implicating CCK in post-
Population studies suggest the presence of a genetic Giardia dyspepsia. In a recent study from China, it was
factor contributing to FD, as there is an increased risk for suggested that mediators derived from mast cells and
dyspepsia in first-degree relatives compared with spouses and enterochromaffin cells, including histamine, tryptase, and
in those with a positive family history of indigestion.93,94 5-HT may be involved in the pathogenesis of PI-FD.110
Several studies have linked FD to a G-protein beta 3 (GNb3) Concerning the role of H. pylori in the pathogenesis of
subunit gene polymorphism (C825T).95–97 FD, although it is associated with a number of organic
A number of recent studies reported associations of causes for dyspepsia, there is little evidence to support a
FD with potentially functional polymorphisms in the COX- causal relationship between H. pylori and FD.111 No con-
1 gene, the COMT gene, the CCK1 receptor, or the Toll- sistent differences in symptom pattern or putative patho-
like receptor 2, but in general these studies suffered from physiological mechanisms have been found between
low individual numbers and lacked detailed pathophysio- H. pylori-positive and H. pylori-negative subjects.3,4,112 The
logical characterization of the patients.98–101 best evidence in support of a role for H. pylori in FD is the
small but statistically significant beneficial effect of erad-
Infection, Inflammation, and the Role of H. Pylori ication therapy on symptoms in FD.113
Bacterial gastroenteritis has been established as one of
the pathogenetic factors of FD in adults.102 A growing Psychosocial Factors
number of studies in the literature provide evidence of Review of the literature clearly reveals an association
persisting low-grade inflammation in patients with post- between psychosocial factors and FD.114–116 The most
infectious FD (PI-FD). In a population-based study from common psychiatric comorbidities in patients with FD are
the United Kingdom, increased duodenal eosinophil counts anxiety disorders, depressive disorders, and somatoform
were associated with FD,103 and in a retrospective study of disorders.117,118 In a clinic-based study, findings showed
155 duodenal biopsy samples that were labeled normal after that 87% of patients with FD, compared with 25% of
routine clinical evaluation, duodenal eosinophilia was patients with organic dyspepsia, had a psychiatric diag-
associated with FD.104 In a study from Leuven,105 focal nosis.117 A large study, utilizing semistructured psychiatric
aggregates of T cells, especially CD8+ cells, were found in interview and psychometric tools, revealed that 34% of the
the PI-FD group only. The number of CD4+ cells in du- FD patients versus 15% of the duodenal ulcer patients had
odenal villi and around crypts was lower, whereas the a psychiatric diagnosis. Anxiety disorders were again the
number of CD68+ cells around crypts was higher in this most common.118 Individuals with FD also seem to expe-
group. As biopsies were taken on average 10 months after rience a greater number of life events which are not limited
symptom onset, they are indicative of persisting changes in to those of negative impact, compared with HCs. A recent
the cellular immunologic response after a previous in- or remote history of abuse is a nonspecific risk factor for
flammatory event, rather than the normal inflammatory symptoms of FD.118 It was often assumed that psycho-
process after the initial GI infection.105 Similar observa- logical distress was a feature of health care seeking patients
tions were confirmed in another study from Japan, which with functional bowel disorders, including FD. Recent
found a high prevalence of histologic duodenitis and studies confirm an association of dyspeptic symptoms in
significantly increased numbers of CCR2-positive macro- the general population with psychosocial factors such as
phages on duodenal biopsies in 136 PI-FD patients com- somatization, anxiety, and life event stress.116,119
pared with HCs.106 Recent data from the Leuven study group have shed
In addition to histologic signs of immune activation light on the role of psychosocial factors in the pathogenesis
in the duodenum, systemic cellular and humoral immune of FD; in 3 studies with >250 FD patients each, it was
responses have also been studied in PI-FD.107 Changes in shown that: (1) somatization and chronic fatigue (CF) were
the cytokine expression profile, such as elevated stimulated significantly associated with impaired quality of life and

physical composite scores. The effects of abuse history and clinician should always keep in mind that also among FD
depression were “mediated” by “somatization.” Trait anx- patients, a high prevalence of unexplained weight loss has
iety, alexithymia, depression, positive effect, negative effect, been observed.48,124
and generalized anxiety disorder were significantly asso-
ciated with impaired quality of life and mental composite FD Subgroups
scores. These data indicate that somatization is the most Studies in tertiary care FD and in uninvestigated
important risk factor for impaired physical health-related dyspepsia in the general population revealed that 40% to
quality of life in FD, whereas mental health-related quality 75% of dyspeptic subjects report symptom aggravation
of life is mainly explained by psychosocial factors120; (2) after ingestion of a meal.7,119,125 Under the assumption that
when the long-term evolution of symptoms and the factors a distinction between meal-related and meal-unrelated
associated with outcome were studied, about half of FD symptoms might be pathophysiologically and clinically
patients reported disappeared or improved symptoms after relevant, the Rome III consensus proposed to consider FD
a mean follow-up of 5 years. Dyspepsia symptom score at an umbrella term and to distinguish the postprandial dis-
initial visit, trait anxiety, and initial weight loss were more tress syndrome (meal-related dyspeptic symptoms, charac-
strongly associated with outcome than gastric sensorimotor terized by postprandial fullness and early satiation) from
function121; (3) somatization is a common risk factor for the epigastric pain syndrome (meal-unrelated dyspeptic
comorbid IBS and CF-like symptoms in FD and mediates symptoms, characterized by epigastric pain and epigastric
the effect of abuse. Gastric sensorimotor function and burning).4 To date, only few studies have evaluated the
depression are specific risk factors for comorbid IBS and Rome III-based subdivision of FD, but the results are
CF-like symptoms, respectively.122 conflicting.125–127
Although these observations show a close interaction
between different psychosocial variables and the presence
and severity of FD symptoms, they do not establish Overlap With Heartburn and IBS
whether they are separate manifestations of a common It is well accepted that heartburn commonly cooccurs
predisposition or whether these psychopathological factors with dyspeptic symptoms, both in the general population
play a causal role in the pathophysiology of dyspeptic and in FD.7,8,128 The Rome II consensus stated that
symptoms. patients with typical heartburn as a dominant complaint
almost invariably have GERD and should be distinguished
from patients with dyspepsia,2 but this approach does re-
liably identify or exclude GERD patients.129,130 The Rome
MANAGEMENT OF UNINVESTIGATED III consensus accepts that heartburn is not a gastro-
DYSPEPSIA duodenal symptom, although it often occurs simulta-
neously with FD symptoms, and its presence does not
History and Clinical Examination exclude the diagnosis of FD.4 Similarly, the frequently
A complete clinical history and a physical examination occurring overlap of FD with IBS131 is explicitly recognized
are important in all patients with dyspepsia. The nature of but does not exclude a diagnosis of FD.4
the symptoms, their frequency and chronicity, the rela-
tionship to ingestion of meals, and a perceived influence of Laboratory Testing
specific dietary factors should all be recorded. The onset of The cost effectiveness of routine laboratory testing,
symptoms (acute or more chronic), the presence of weight especially in younger patients with uncomplicated dyspep-
loss, and other alarm symptoms such as anemia, blood loss, sia, has not been established. Nevertheless, most clinicians
or dysphagia are also relevant. In case of long-standing will consider routine tests after the age of 45 to 55 years.
symptoms, the reason for the current health care seeking Other studies such as serum amylase, antibodies for celiac
should be elicited, so that specific fears and concerns can be sprue, stool testing for ova and parasites or Giardia anti-
detected. The use of prescription and nonprescription gen, and pregnancy tests may be considered in selected
medications should be reviewed, and medications com- cases.
monly associated with dyspepsia (especially NSAIDS)
should be discontinued if possible. In cases where NSAIDS Initial Management Strategies
discontinuation is not allowed, a trial of PPIs can be con-
sidered, although many guidelines recommend endoscopic Medical history and physical examination will allow in
evaluation to exclude peptic ulcer disease. distinguishing dyspepsia from symptoms that are suggestive
of esophageal, pancreatic, or biliary disease in most cases.
However, history, clinical findings, and even the presence of
The Dyspepsia Symptom Complex
alarm symptoms, are unreliable parameters in distinguishing
Symptom Pattern and Heterogeneity functional from organic causes of dyspepsia, both by primary
The dyspepsia symptom complex is broader than the 4 care physicians and by gastroenterologists.20,23,24,132,133
cardinal symptoms that constitute the Rome III definition Hence, most guidelines and recommendations encourage the
and includes multiple symptoms such as epigastric pain, use of prompt endoscopy in case of risk factors like NSAID
bloating, early satiety, fullness, epigastric burning, belching, use, age above a threshold, and alarm symptoms.134–136 The
nausea, and vomiting. Although often chronic, the symp- optimal management strategy for the majority of patients
toms in FD are mostly intermittent, even during highly who do not fulfill these alarm or risk criteria remains a matter
symptomatic episodes.3,6 The most prevalent symptoms are of debate and controversy, and several approaches have been
postprandial fullness and bloating, followed by epigastric proposed: (1) prompt diagnostic endoscopy, followed by
pain, early satiety, nausea, and belching.3,10,34,48,49,123 targeted medical therapy; (2) noninvasive testing for H. pylori
Weight loss is traditionally considered an alarm symptom, infection, followed by treatment based on the result (“test
pointing toward potentially serious organic disease, but the and treat”); and (3) empirical antisecretory therapy. In the 2

latter strategies, endoscopy is performed in nonresponders or potentially curable upper GI malignancies.134–136 The ra-
those with recurrent symptoms. tionale for this approach is the fact that the vast majority of
gastric malignancies occur in patients above 45 years of
Prompt Endoscopy and Directed Treatment age.141–143 However, most patients with newly diagnosed
Diagnostic upper GI endoscopy offers direct recog- gastric cancer are already incurable at the time of diagnosis,
nition of organic causes of dyspepsia such as peptic ulcer, and many of these will have some alarm feature that would
erosive esophagitis, or malignancy137 (Fig. 2). The proce- have warranted immediate endoscopy.143 In patients below
dure may also have a reassurance effect on physicians and 45 years of age, with a family history of gastric cancer, or
patients.138–140 Gastric mucosal biopsies allow diagnosing who emigrated from countries with high rates of gastric
H. pylori infection, followed by eradication therapy if cancer, or who have had partial gastrectomy, early endo-
positive. It has been claimed that endoscopy may diagnose scopy is also recommended.
early gastric cancer at a curable stage, but this is relatively
rare and evidence for the claim is at the best weak.141–143 Test and Treat for H. pylori Infection
However, endoscopy is also expensive and invasive H. pylori is causally associated with peptic ulcer dis-
and may not have a major impact on treatment after all. ease and is the most important risk factor for gastric can-
Patients with peptic ulcer or erosive esophagitis will receive cer.148 Hence, several consensus panels support noninvasive
antisecretory therapy. In those with negative upper endo- testing for H. pylori in young patients (below 45 to 55 y)
scopy, FD and nonerosive GERD are likely diagnoses, and with uncomplicated dyspepsia. Patients with a positive test
both can also be treated empirically with antisecretory result should receive eradication therapy (a PPI plus 2 an-
therapy. In contrast, it has been argued that initial em- tibiotics, such as amoxicillin and clarithromycin, for 10 to
pirical antisecretory therapy will only delay the endoscopy, 14 d), whereas patients with a negative test result should be
as both FD and GERD are likely to recur after discontin- treated empirically, usually with a PPI. The benefits of this
uation of empirical therapy at which time they will be re- “test-and-treat” strategy are the cure of peptic ulcer disease
ferred for endoscopy. or prevention of future peptic ulcers, and also the cure of a
A number of randomized controlled trials (RCTs) small subset (approximately 7%) of patients with FD who
have compared prompt endoscopy with empirical non- are H. pylori infected.149,150 Eradication of H. pylori elim-
invasive management strategies. A meta-analysis of 5 trials inates chronic gastritis and this may, theoretically, con-
comparing initial endoscopy to a “test-and-treat” strategy tribute to a reduction of risk of H. Pylori-associated gastric
concluded that initial endoscopy may be associated with a cancer.151
small reduction in the risk of recurrent dyspeptic symptoms In contrast, in western countries, the prevalence of
but that this gain was not cost effective.144 Most studies H. pylori infection in patients with uninvestigated dyspepsia
found higher direct and indirect costs associated with is rapidly declining, and infection rates are especially low in
prompt endoscopy, which were not completely offset by those below 30 years of age (10% to 30%). Widespread use
reduced medication use or subsequent physician vis- of antibiotics has the disadvantage of inducing resistance
its.145–147 The available data, therefore, do not support and occasional occurrence of drug allergies. Whether
early endoscopy as cost-effective initial management strat- eradication of H. pylori causes or worsens GERD has not
egy for all patients with uncomplicated dyspepsia. been proven and is an ongoing matter of controversy.148,152
Nevertheless, most available practice guidelines will Furthermore, the accuracy of noninvasive test depends on
advocate initial endoscopy in all patients above a certain the prevalence of H. pylori in the population as well as the
age threshold, usually 45 to 55 years old, in order to detect sensitivity and specificity of the test. Serologic tests are the
least expensive and the least accurate tests. If the prevalence
of H. pylori in a population is < 60%, the fecal antigen test
and urea breath test for H. pylori are preferred, because
their higher accuracy reduces inappropriate treatment for
patients without H. pylori infection.153
Randomized placebo-controlled trials showed only a
modest reduction of dyspepsia symptoms after a “test-and-
treat” approach in primary care.154–156 A meta-analysis of
studies comparing “test and treat” to empirical anti-
secretory therapy in dyspepsia found little difference in
symptom resolution or costs between the 2 strategies.157
Although earlier models assuming higher prevalences sug-
gested a higher benefit,158–160 recent economic models
suggest that the “test and treat” may be equally or less cost
effective compared with empirical antisecretory ther-
apy.161,162 Therefore, “testing and treating” for H. pylori as
an initial approach is currently most likely to be beneficial
in areas with a high infection rate.
Empiric Antisecretory Therapy

Initial empirical antisecretory therapy is widely used in
primary care for patients with uninvestigated dyspepsia.
This approach is attractive, because it can control symp-
FIGURE 2. Management algorithm of uninvestigated chronic toms and eliminate lesions in most patients with underlying
dyspeptic symptoms. GERD or peptic ulcer disease and may be beneficial for up

to one third of patients with FD.163,164 PPIs provide su- MANAGEMENT OF FD

perior symptom relief compared with H2-receptor blockers,
and the response usually occurs within 2 weeks of therapy.145 General Measures
Disadvantages of empirical PPI therapy are the rapid Reassurance and education is important in FD. De-
symptom relapse after cessation of therapy and the poten- spite the normal findings at endoscopy, it is important to
tially related occurrence of rebound acid hypersecre- provide a confident and positive diagnosis. In IBS, it has
tion.162,163 Many patients, therefore, will go on to chronic been shown that a positive physician-patient interaction
PPI therapy. can reduce the health care seeking, and these principles are
As indicated above, a meta-analysis of studies com- probably also valid for FD, although a recent study failed
paring “test and treat” to empirical antisecretory therapy in to show a reassurance effect after negative endoscopy.165,166
dyspepsia found little difference in symptom resolution or Lifestyle and dietary measures are usually prescribed
costs between the 2 strategies,157 but recent economic to FD patients, but the impact of dietary interventions has
analyses indicate that empirical antisecretory therapy may not been systematically studied.5 It seems logical to have
be equally or more cost effective, and this is likely to in- patients eat more frequent, smaller meals. Because the
crease as PPI cost has been steadily decreasing.161,162 presence of lipids in the duodenum enhances gastric sensi-
tivity, avoiding meals with a high fat content might be
advisable.70,71 Likewise, doctors tend to discourage con-
Recommendations sumption of spicy foods containing capsaicin and other
In patients older than 45 to 55 years without alarm irritants.32 Coffee may aggravate symptoms in some cases167
features, most guidelines will recommend initial diagnostic and, if implicated, should be avoided. Stopping smoking
endoscopy, although the benefit in terms of detection of and ceasing consumption of alcohol are suggested to be
early stage malignancies remains unproven. In these cases, helpful, but there is no convincing evidence of efficacy.168
management will depend on endoscopic findings and The avoidance of aspirin and other NSAIDs is commonly
detection of H. pylori, but PPI therapy is likely to be recommended and seems sensible, although not of estab-
prescribed to the majority of patients. lished value.25,32 If the patient has an apparent coexistent
In a young dyspeptic patient (below the age of 45 to anxiety disorder or depression, appropriate treatment
50 y) without alarm features, systematic initial endoscopy should be considered.
cannot be recommended because the yield is low and it is
unlikely to lead to improved outcomes. In a population Pharmacological Treatments
with high prevalence (> 20%) of H. pylori infection, the
test-and-treat approach remains attractive, as it will Acid-suppressive Drugs
cure patients with peptic ulcer disease. In those who are On the basis of meta-analyses of therapeutic outcomes
H. pylori-negative, a PPI can be prescribed for 1 to 2 in FD, efficacy of antacids, sucralfate, and misoprostol has
months. In populations where the prevalence of H. pylori not been demonstrated.169
infection is low, empirical antisecretory therapy (a PPI for
1 to 2 months) seems to be the preferred option. Those who PPIs
fail to respond to these initial approaches, and possibly In a recently updated meta-analysis by Moayyedi
those with symptom recurrence after cessation of anti- et al170 from 10 RCTs evaluating 3347 participants, the
secretory therapy, should undergo endoscopy, although the average response to PPI therapy was 34%, compared with a
yield is likely to be low. 25% response to placebo. Overall there was a statistically
significant benefit of PPI over placebo, and number needed
to treat was 10. The relative risk reduction (13%) was lower
Additional Investigations than for H2 blockers (23%), probably reflecting more strict
Additional investigations may be pursued in patients inclusion criteria and better exclusion of GERD. Increasing
with progressive or refractory symptoms that do not re- the dose from half to full or double dose did not affect the
spond to initial management approaches. Testing for celiac response to PPI therapy. Subgrouping of FD using pre-
disease and Giardia infection is useful in refractory symp- vious Rome definitions showed a trend for PPI therapy to
toms, especially when accompanied by weight loss. In be most effective in the group with overlapping reflux, less
patients with severe pain or weight loss, abdominal ultra- effective in the epigastric pain group, and lacking a stat-
sonography or computed tomography scans can be used to istically significant effect in the dysmotility group.171
rule out pancreatic or biliary disease and to screen for
stenosis of large abdominal arteries. H2 blockers
In case of severe postprandial fullness, and especially A meta-analysis of 12 randomized placebo-controlled
in case of refractory nausea and vomiting, gastric emptying trials evaluating the efficacy of H2RA in FD, in a total of
testing using scintigraphy or the breath test can be con- 2183 patients, reported that an average of 54% of partic-
sidered. In case of severe delay, a small-bowel x-ray or ipants had an improvement in dyspepsia with H2RA ther-
computed tomography enterography can rule out mech- apy compared with 40% in the placebo group. Overall there
anical stenosis as a contributing factor. In case of refractory was a statistically significant benefit of H2RAs over placebo
intermittent pain or epigastric burning, esophageal pH/ in terms of improvement of dyspepsia. The number needed
impedance monitoring is useful to diagnose atypical man- to treat to improve one case of dyspepsia that would not
ifestations of GERD not sufficiently responding to em- have been improved by placebo was 7.170 H2 blockers thus
pirical antisecretory therapy. Psychological or psychiatric seem to be efficacious in FD. However, many of these
assessment is recommended in case of long-standing re- trials probably included GERD patients under a broad
fractory or debilitating symptoms or in case of unexplained interpretation of FD, which may account for much of the
major weight loss. benefit.

Eradication of H. pylori Infection was obtained in one study, but not in the other, and overall
There is evidence of a small but significant benefit in therapeutic gain seemed small. The drug was well tolerated
eradicating H. pylori in FD. The updated Cochrane review in this FD program, but was meanwhile withdrawn for
included 18 RCTs.113 These trials compared antisecretory increased incidence of cardiovascular ischemic events. One
dual or triple therapy with placebo antibiotics ± anti- potential novel approach is a combination of mechanisms.
secretory therapy, and evaluated dyspepsia at 3 to 12 A phase 2 study with itopride, a combined D2 antagonist
months. Seventeen of these trials gave results as dichoto- and cholinesterase inhibitor, suggested efficacy in FD.180
mous outcomes, evaluating 3566 patients, and there was no However, the phase 3 program with this drug in FD was
significant heterogeneity between the studies. There was a not able to confirm efficacy.181 The reasons for the dis-
10% relative risk reduction for persisting symptoms in the crepancy are unclear, but the strict exclusion of coexisting
H. pylori eradication group compared with placebo. The heartburn in phase 3, unlike phase 2, may have contributed.
number needed to treat to cure one case was 14. A further 3 Motilin and ghrelin receptors are other targets that are
trials compared bismuth-based H. pylori eradication with under evaluation for the treatment of upper GI motor
an alternative pharmacological agent. These trials were disorders. The use of motilin receptor agonist as a target for
smaller and had a shorter follow-up but suggested that prokinetic actions is not novel, and erythromycin is clin-
H. pylori eradication was more effective than either H2RAs ically applied as a motilin receptor agonist, for instance to
or sucralfate in treating nonulcer dyspepsia. It seems that facilitate gastric emptying and tolerance of intragastric
H. pylori eradication therapy has a small but statistically nutrition in critically ill patients.182 Azithromycin is an-
significant effect in H. pylori-positive FD. other macrolide antibiotic that is devoid of inhibition of
Arguments against eradication therapy are the low cytochrome isoenzymes. In a study that used small-bowel
number of responders, and the delayed occurrence of the manometry to evaluate the effects of azithromycin and
demonstrable symptomatic benefit. In contrast, it has been erythromycin administered intravenously, azithromycin
argued that H. pylori eradication can induce sustained re- was at least as potent as erythromycin in stimulating antral
mission but in a small minority of patients.172 Other argu- contractility.183 Azithromycin may, therefore, provide an
ments in favor of the use of eradication therapy are the alternative to erythromycin for gastroprokinetic applica-
protection against peptic ulcer, putative protection against tions. Novel motilin receptor agonists are being developed
gastric cancer, and the short-term nature and relatively low for these therapeutic indications. These include mitemcinal
cost of the treatment.172 (GM 611) and GSK962040, a small molecule motilin ago-
nist.184–186 The ghrelin receptor is a related receptor, with
established prokinetic effects upon acute intravenous ad-
Drugs That Alter Gastric Sensorimotor Function
ministration of ghrelin.187,188 In a pilot study in 6 FD pa-
Prokinetic Agents tients with reduced food intake, intravenous administration
Pharmacological approaches to correct abnormal of ghrelin twice daily for 2 weeks increased hunger ratings
gastric motility or sensitivity are considered a valid ther- and tended to stimulate food intake. The infusions were
apeutic approach in upper GI motor disorders. GI proki- well tolerated.189 TZP-101 is a novel intravenously ad-
netics, drugs that stimulate gastric smooth muscle ministered ghrelin agonist, under development for the
contractions, have long been considered the drugs of choice treatment of gastroparesis and postoperative ileus. Initial
for the treatment of FD and gastroparesis.173 Traditional human studies with intravenous administration of 20 to
prokinetic agents are dopamine2 receptor (D2) antagonists 600 mg/kg confirmed a favorable pharmacokinetic, phar-
or 5-HT4 receptor agonists. A meta-analysis, mainly based macodynamic, and safety profile.190 TZP, an orally avail-
on studies with domperidone and cisapride, suggested su- able ghrelin agonist, is under development for the treatment
periority of prokinetics to placebo in FD, with a relative of gastroparesis.191
risk reduction of 33% and a number needed to treat of 6,170
and separate analyses also suggested efficacy for cisapride Fundus-relaxing Drugs
and domperidone.174 Metoclopramide and domperidone Impaired gastric accommodation and visceral hyper-
are D2 antagonists with a stimulatory effect on upper GI sensitivity, using fundic relaxants or visceral analgesics, are
motility. Unlike metoclopramide, which may cause serious other potentially attractive targets for drug development in
neurological adverse effects, domperidone does not cross sensorimotor disorders of the upper GI tract. The anx-
the blood-brain barrier. Cisapride facilitates the release of iolytic 5-HT1A agonist buspirone was shown to dose de-
acetylcholine in the myenteric plexus through 5-HT4 re- pendently relax the proximal stomach in HCs,192 suggesting
ceptor agonist and accelerates gastric emptying. Mosapride, a therapeutic potential for this class of drugs in the treat-
which similar to cisapride is a mixed 5-HT4 receptor agonist ment of FD. A Japanese placebo-controlled study with the
and 5-HT3 receptor antagonist, demonstrated no benefit anxiolytic 5-HT1A agonist tandospirone 10 mg t.i.d.
when compared with placebo in a large European study.175 showed significant improvements in upper abdominal pain
However, a critical evaluation of these older prokinetics and discomfort and significant improvements in the state-
shows that the evidence of their efficacy is in fact limited trait anxiety inventory questionnaire and quality of life
and would not meet the current requirements for clinical assessed with the Short Form-8. Although anxiety and
efficacy trials.176 Furthermore, cisapride has been with- Short Form-8 scores did not differ between both treatment
drawn because of QT-prolongation, and supratherapeutic arms, the improvement in trait anxiety scores was higher in
doses of domperidone may also prolong the QT interval. responders to tandospirone. These observations suggest
More recently, development of new prokinetic drugs has that central effects may have contributed to the therapeutic
not been very successful and there is a clear need for novel effect of tandospirone.193 Acotiamide is a novel compound
approaches and new targets.177,178 Tegaserod, a 5-HT4 re- that enhances acetylcholine release through the M1 and M2
ceptor agonist, was evaluated in 2 phase 3 RCTs in women muscarinic receptors antagonists and was shown to en-
with dysmotility-like FD.179 Statistically, significant benefit hance gastric accommodation in animal studies.194,195 In a

study on rats, acotiamide restored delayed gastric emptying Other Pharmacotherapeutic Approaches
and feeding inhibition induced by restraint stress, and this Iberogast is an herbal mixture with beneficial effects on
was accompanied by decreased hypothalamic expression of FD symptoms based on placebo-controlled studies, but the
neuromedin U, a messenger involved in mediating effects of underlying mechanism of action is unclear.208 In a multi-
stress on the control of upper GI functions.196 In conscious center placebo-controlled study from Germany, gastric
dogs, acotiamide inhibited recombinant human and canine emptying was measured in 103 FD patients before treat-
stomach-derived acetylcholinesterase activity in vitro.197 ment and repeated after 4 weeks of therapy in those with
Unlike itopride or mosapride, acotiamide showed no delayed emptying. Significantly higher treatment response
affinity for dopamine D2 or serotonin 5-HT4 receptors. was observed with iberogast, but this was not associated
With regard to cardiovascular side effects, unlike cisapride, with enhanced gastric emptying.209
acotiamide did not affect myocardial monophasic action
potential duration, QT interval, or corrected QT interval in Psychological Interventions
anesthetized dogs. These results suggest that acotiamide
Studies have shown that FD patients have a higher
stimulates gastric motility in vivo by inhibiting acetylcho-
prevalence of psychosocial comorbidity, although the role
linesterase activity without affecting QT interval. In a
in symptom generation remains unclear. In part on the
European phase IIa trial comparing placebo, 50, 100, and
basis of these comorbidities, psychological interventions
300 mg doses, a 100 mg dose of acotiamide 3 t.i.d. improved
such as group support with relaxation training, cognitive
FD symptoms and quality of life, and this was at least in
therapy, psychotherapy, and hypnotherapy have been used
part attributed to an improvement of gastric accom-
in FD. A systematic review of clinical trials of psychological
modation.198 In 2 similar phase II trials in Japan, which
interventions for FD found that all trials claimed benefit
included 1156 patients and evaluated doses between 50 and
from psychological interventions, with effects persisting for
200 mg, a 100 mg dose was found to be superior to placebo
over 1 year, but all studies suffered from inadequate stat-
in alleviating meal-related symptoms in FD.199 A Japanese
istical analysis.210 The authors concluded that there is in-
phase III trial with acotiamide in FD showed superiority
sufficient evidence to confirm the efficacy of psychological
over placebo in improving or eliminating symptoms of early
interventions in FD.210
satiation and postprandial fullness.200,201
Candidate agents for the treatment of visceral hyper-
sensitivity involve tachykinin antagonists and peripherally Recommendations
acting opioid agonists. The NK1 receptor antagonist In FD patients with mild or intermittent symptoms,
aprepitant did not affect GI motor function in a placebo- reassurance, education, and some dietary changes may be
controlled crossover study in HCs.202 In a small (n = 40) sufficient. Drug therapy can be considered in patients with
8-week RCT of the peripherally acting k-opioid agonist more severe symptoms, or those who do not respond to
asimadoline (0.5 or 1 mg) in FD, the drug had no significant reassurance and lifestyle changes. Testing for H. pylori in-
effect on symptoms or nutrient tolerance compared with fection is recommended and, if positive, eradication therapy
placebo.203 can be prescribed. However, an immediate impact on
symptoms is unlikely, and any potential benefit is mainly
Antidepressants observed over longer follow-up. Both PPIs and prokinetics
In the absence of specific visceral analgesics, tricyclic can be used in initial pharmacotherapy. The symptom
antidepressants and other centrally acting drugs are often pattern may help in determining the most appropriate ini-
used assuming that they decrease visceral sensitivity. A tial choice, but a change of drug class is advisable in case of
meta-analysis of the available literature suggests that both insufficient therapeutic response.
centrally acting drugs (antidepressants and anxiolytics) and A trial of PPI therapy, preferably 4 weeks or more,
peripherally acting drugs (prokinetics and antisecretory should be given to all patients with coexisting heartburn,
agents) are associated with a significant pain reduction in and also in those with epigastric pain or burning (epigastric
FD.204 Nevertheless, the underlying mechanism remains pain syndrome). In case of symptomatic relief, interruption
unclear, and both central effects (anxiety, depression, or of treatment should be tried and intermittent or chronic
somatization) and peripheral effects (altered motility) have therapy with a PPI (or H2RA) can be used for patients with
been implicated in the therapeutic efficacy of tricyclics and repeated relapses. In those with postprandial fullness and
other agents. van Kerkhoven et al205 conducted an 8-week early satiation, a prokinetic with an attractive safety profile
controlled trial of venlafaxine, a noradrenaline and sero- (eg, domperidone when available) can be considered. Me-
tonin reuptake inhibitor, in 160 FD patients. Venlafaxine toclopramide and cisapride should not be used because of
had no favorable effect over placebo on symptom severity their risk of serious adverse events. Although in theory
or symptom resolution. Furthermore, a very high dropout combinations of PPIs and prokinetics may have additive
rate occurred during venlafaxine therapy.205 Although this symptomatic effects, single drug therapy is preferable.
study does not fully exclude a therapeutic potential for In patients with bothersome symptoms that persist
antidepressants in FD, the class of noradrenaline and se- despite these initial therapies, a trial of low-dose tricyclic
rotonin reuptake inhibitors is best avoided.206 The efficacy antidepressants may be considered, even in the absence of
of flupenthixol and melitracen, a combination preparation apparent anxiety or depression. Higher doses can be con-
with anxiolytic and antidepressant properties, was assessed sidered in case of important anxious or depressive co-
in a randomized controlled crossover trial in 25 FD patients morbidity. It seems advisable to avoid selective serotonine
from Lebanon. Eight weeks of flupenthixol and melitracen and noradrenaline reuptake inhibitors. A trial of simethi-
was superior to placebo in providing improvement in sub- cone, medically prescribed herbal preparations with appa-
jective global symptom ratings and quality of life. The rent benefit in controlled trials, or bismuth salts may also be
treatment was well tolerated, and depression or anxiety considered in refractory patients. In case of debilitating
comorbidity did not predict symptom responsiveness.207 epigastric pain, symptomatic analgesics, up to opioids,

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Organic Versus Functional: Dyspepsia

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CLINICAL REVIEW

ranging from pain or discomfort to postprandial fullness,

D yspepsia is the medical term used to describe the sense

J Clin Gastroenterol Volume 46, Number 3, March 2012 www.jcge.com | 175

Peptic Ulcer Intolerance to Food or Drugs

176 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 177

178 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 179

180 | www.jcge.com r 2012 Lippincott Williams & Wilkins

Empiric Antisecretory Therapy

r 2012 Lippincott Williams & Wilkins www.jcge.com | 181

to one third of patients with FD.163,164 PPIs provide su- MANAGEMENT OF FD

182 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 183

184 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 185

186 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 187

188 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 189

190 | www.jcge.com r 2012 Lippincott Williams & Wilkins

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Organic Versus Functional: Dyspepsia

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Organic Versus Functional: Dyspepsia

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CLINICAL REVIEW

ranging from pain or discomfort to postprandial fullness,

D yspepsia is the medical term used to describe the sense

J Clin Gastroenterol  Volume 46, Number 3, March 2012 www.jcge.com | 175

Peptic Ulcer Intolerance to Food or Drugs

176 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 177

178 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 179

180 | www.jcge.com r 2012 Lippincott Williams & Wilkins

Empiric Antisecretory Therapy

r 2012 Lippincott Williams & Wilkins www.jcge.com | 181

to one third of patients with FD.163,164 PPIs provide su- MANAGEMENT OF FD

182 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 183

184 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 185

186 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 187

188 | www.jcge.com r 2012 Lippincott Williams & Wilkins

r 2012 Lippincott Williams & Wilkins www.jcge.com | 189

190 | www.jcge.com r 2012 Lippincott Williams & Wilkins

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J Clin Gastroenterol Volume 46, Number 3, March 2012 www.jcge.com | 175