Dyspepsia

CHAPTER
14
Dyspepsia
JAN TACK
CHAPTER OUTLINE
Definition...................................................................................194 Approach to Uninvestigated Dyspepsia......................................200
Organic Causes of Dyspepsia....................................................194 History and Physical Examination............................................... 200
Intolerance to Food or Drugs..................................................... 195 Laboratory Testing..................................................................... 200
PUD.......................................................................................... 195 Initial Management Strategies.................................................... 200
GERD........................................................................................ 195 Additional Investigations............................................................ 202
Gastric and Esophageal Cancer................................................. 195 Treatment of Functional Dyspepsia...........................................202
Pancreatic and Biliary Tract Disorders........................................ 195 General Measures..................................................................... 202
Other GI or Systemic Disorders.................................................. 196 Pharmacologic Treatment.......................................................... 202
Functional Dyspepsia.................................................................196 Psychological Interventions........................................................ 204
Dyspepsia Symptom Complex.................................................... 196 Recommendations.....................................................................205
Epidemiology............................................................................. 198
Pathophysiology........................................................................ 198
Pathogenic Factors.................................................................... 199
(postprandial fullness, early satiation, epigastric pain, epigas-

DEFINITION tric burning) are now considered specific for a gastroduodenal
origin, although other symptoms are acknowledged to coexist
Dyspepsia is derived from the Greek words δυς- (dys-) and with dyspepsia.
πέψη (pepse) and means “difficult digestion.” In current In patients with dyspepsia, additional clinical investiga-
medical terminology, dyspepsia refers to a heterogeneous tions may identify underlying organic disease that is likely to
group of symptoms located in the upper abdomen. Dyspepsia cause the symptoms. In these persons, symptoms are due to
is often broadly defined as pain or discomfort centered in the an organic cause of dyspepsia (Box 14-1), but in the majority
upper abdomen1,2 but may include varying symptoms like of persons with dyspeptic symptoms, no organic abnormality
epigastric pain, postprandial fullness, early satiation, anorexia, is identified by routine clinical evaluation (including endos-
belching, nausea and vomiting, upper abdominal bloating, copy), and these patients are considered to have functional
and even heartburn and regurgitation. Patients with dyspep- dyspepsia. The term uninvestigated dyspepsia refers to dyspep-
sia commonly report several of these symptoms.3 tic symptoms in persons in whom no diagnostic investigations
Consensus definitions of dyspepsia and functional dys- have yet been performed and a specific diagnosis that explains
pepsia have been proposed. The overlap between symptoms the dyspeptic symptoms has not been determined.
of gastric origin and symptoms of presumed esophageal
origin (especially GERD) has remained an area of controversy.
With time, definitions of dyspepsia have evolved to become
more restrictive and more focused on symptoms thought to ORGANIC CAUSES OF DYSPEPSIA
arise from the gastroduodenal region, not the esophagus.
Earlier definitions considered dyspepsia to comprise all The most prevalent identifiable causes underlying dyspeptic
upper abdominal and retrosternal sensations—in effect, all symptoms are PUD and GERD. Malignancies of the upper GI
symptoms considered to be referable to the proximal alimen- tract and celiac disease are less common but clinically impor-
tary tract.4 The Rome I and II Consensus Committees both tant organic causes of dyspepsia6-10 (see Box 14-1). The inves-
defined dyspepsia as pain or discomfort centered in the upper tigation of choice in persons with dyspepsia is endoscopy,
abdomen.1,2 Discomfort includes postprandial fullness, upper which allows identification of erosive esophagitis, Barrett’s
abdominal bloating, early satiation, epigastric burning, belch- esophagus, peptic ulcer, and gastric or esophageal cancer.
ing, nausea, and vomiting. Heartburn may occur as part of the Systematic studies indicate that 20% to 25% of patients
symptom constellation, but the Rome II committee decided with dyspeptic symptoms in Western societies have erosive
that when heartburn is the predominant symptom, the patient esophagitis, 20% have endoscopy-negative GERD, 10% have
should be considered to have GERD, not dyspepsia. peptic ulcer, 2% have Barrett’s esophagus, and 1% or less have
The Rome III Consensus Committee defined dyspepsia as malignancy.6,10 Minor findings like duodenitis or gastritis do
the presence of symptoms considered by the physician to not seem to correlate with the presence or absence of dyspeptic
originate from the gastroduodenal region.5 Only 4 symptoms symptoms.
194
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Chapter 14 Dyspepsia 195
BOX 14-1 Causes of Dyspepsia
Luminal GI Tract Medications

Functional dyspepsia Acarbose
Chronic gastric volvulus Aspirin and other NSAIDs (including COX-2 selective agents)
Chronic gastric or intestinal (mesenteric) ischemia Colchicine
Food intolerance Digitalis preparations
Gastric or esophageal neoplasm Estrogens
Gastric infections (cytomegalovirus, fungus, tuberculosis, Ethanol
syphilis) Gemfibrozil
Gastroparesis (diabetes mellitus, postvagotomy, scleroderma, Glucocorticoids
chronic intestinal pseudo-obstruction, postviral, idiopathic) Iron
GERD Levodopa
Infiltrative gastric disorders (Ménétrier’s disease, Crohn’s Narcotics
disease, eosinophilic gastroenteritis, sarcoidosis, Niacin
amyloidosis) Nitrates
IBS Orlistat
Parasites (Giardia lamblia, Strongyloides stercoralis) Potassium chloride
PUD Quinidine
Sildenafil
Systemic Conditions Theophylline
Adrenal insufficiency
Diabetes mellitus Pancreaticobiliary Disorders
Heart failure, myocardial ischemia Biliary pain: cholelithiasis, choledocholithiasis, sphincter of Oddi
Intra-abdominal malignancy dysfunction
Pregnancy Chronic pancreatitis
Renal insufficiency Pancreatic neoplasms
Thyroid disease, hyperparathyroidism
Intolerance to Food or Drugs GERD

Contrary to popular beliefs, ingestion of specific foods (e.g., Erosive esophagitis is a diagnostic marker for GERD, but
spices, coffee, alcohol) or excessive amounts of food has most patients with symptoms due to reflux of stomach
never convincingly been established as causing dyspepsia.11,12 contents into the esophagus have no endoscopic signs of
Although ingestion of food often aggravates dyspeptic symp- esophageal erosion or nonerosive GERD. Erosive esophagitis
toms, the effect is probably related to the sensorimotor is found in some 20% of dyspeptic patients, and a similar
response to food rather than specific food intolerances or aller- frequency of patients may have nonerosive GERD.6,10 Empiri-
gies. Acute ingestion of capsaicin induces dyspeptic symp- cal use of acid-suppressive therapy decreases the likelihood
toms in healthy persons and those with functional dyspepsia, of finding erosive esophagitis in persons with dyspepsia (see
with greater intensity in the latter group.13 Chapter 44).
Dyspepsia is a common side effect of many drugs,
including iron, antibiotics, narcotics, digitalis, estrogens and
oral contraceptives, theophylline, and levodopa. Medications
Gastric and Esophageal Cancer
may cause symptoms through direct gastric mucosal injury, The risk of gastric or esophageal malignancy in patients
changes in GI sensorimotor function, provocation of gastro- with dyspeptic symptoms is estimated to be less than 1%.9 The
esophageal reflux, or idiosyncratic mechanisms. NSAIDs have risk of gastric cancer is increased among persons with Hp
received the most attention because of their potential to induce infection, a family history of gastric malignancy, or a history
ulceration in the GI tract. Chronic use of aspirin and other of gastric surgery or immigration from an area endemic for
NSAIDs may provoke dyspeptic symptoms in up to 20% of gastric malignancy. The risk of esophageal cancer is increased
persons, but the occurrence of dyspepsia correlates poorly in men, smokers, persons with high alcohol consumption, and
with the presence of ulcers. In controlled trials, dyspepsia those with a long-standing history of heartburn (see Chapters
developed in 4% to 8% of persons treated with NSAIDs, with 47 and 54).
an odds ratio ranging from 1.1 to 3.1 compared with placebo.
The magnitude of this effect depends on the dose and type of
NSAID.14 Compared with NSAIDs, COX-2 selective inhibitors
Pancreatic and Biliary Tract Disorders
are associated with a lower frequency of dyspepsia and peptic Despite the high prevalence of both dyspepsia and gallstones
ulceration.15 in adults, epidemiologic studies have confirmed that choleli-
thiasis is not associated with dyspepsia. Persons with dyspep-
sia should not be routinely investigated for cholelithiasis,
and cholecystectomy in persons with cholelithiasis is not
PUD indicated for dyspepsia alone. The clinical presentation of
Peptic ulcer is a well-established cause of dyspeptic symptoms biliary pain is easily distinguishable from that of dyspepsia
and an important consideration in patients with dyspepsia, (see Chapter 65).
but the frequency of peptic ulcer in persons with dyspepsia Pancreatic disease is less prevalent than cholelithiasis, but
is only 5% to 10%.6,10,14 Increasing age, NSAID use, and symptoms of acute or chronic pancreatitis or of pancreatic
Hp infection are the main risk factors for peptic ulcer (see cancer may initially be mistaken for dyspepsia. Pancreatic
Chapters 51 and 53). disorders are usually associated with more severe pain and
196 Section III Symptoms, Signs, and Biopsychosocial Issues
often accompanied by anorexia, rapid weight loss, or jaundice

(see Chapters 58 to 60). BOX 14-2 Classification of and Diagnostic Criteria for
Functional Dyspepsia, Postprandial Distress Syndrome,
and Epigastric Pain Syndrome*
Other GI or Systemic Disorders
Functional Dyspepsia†
Several GI disorders may cause dyspepsia-like symptoms: Includes 1 or more of the following:
infectious (e.g., Giardia lamblia, Strongyloides stercoralis, tuber- 1. Bothersome postprandial fullness
culosis, fungi, syphilis), inflammatory (celiac disease, Crohn’s 2. Early satiation
disease, sarcoidosis, lymphocytic gastritis, eosinophilic gastro- 3. Epigastric pain
enteritis), or infiltrative (lymphoma, amyloidosis, Ménétrier’s 4. Epigastric burning
disease) disorders of the upper GI tract or stomach. Most of and
these causes will be identifiable by upper GI endoscopy with No evidence of structural disease (including at upper
mucosal biopsies. Recurrent gastric volvulus and chronic endoscopy) that is likely to explain the symptoms
mesenteric or gastric ischemia may present with dyspeptic
symptoms (see Chapters 26, 29 to 31, 36, 107, 113, 115, and Postprandial Distress Syndrome†
Must include 1 or both of the following:
118). The symptom pattern associated with gastroparesis
1. Bothersome postprandial fullness, occurring after ordinary-
(idiopathic, drug-induced, or secondary to metabolic, sys- sized meals, at least several times per week
temic, or neurologic disorders) is similar to dyspepsia, and the 2. Early satiation that prevents finishing a regular meal, at least
distinction between idiopathic gastroparesis and functional several times per week
dyspepsia with delayed gastric emptying is not well defined
(see later and Chapter 49). Dyspepsia may be the presenting Supportive Criteria
or accompanying symptom of acute myocardial ischemia, 1. Upper abdominal bloating or postprandial nausea or
pregnancy, acute or chronic renal failure, thyroid dys excessive belching can be present
function, adrenal insufficiency, or hyperparathyroidism (see 2. Epigastric pain syndrome may coexist
Chapters 36 and 39). Epigastric Pain Syndrome†
Must include all of the following:
1. Pain or burning localized to the epigastrium of at least
FUNCTIONAL DYSPEPSIA moderate severity, at least once per week
2. Pain is intermittent
According to the Rome III criteria, functional dyspepsia is 3. Not generalized or localized to other abdominal or chest
defined as the presence of early satiation, postprandial full- regions
ness, epigastric pain, or epigastric burning in the absence of 4. Not relieved by defecation or passage of flatus
organic, systemic, or metabolic disease that is likely to explain 5. Not fulfilling criteria for gallbladder or sphincter of Oddi
the symptoms5 (Box 14-2). disorders
Supportive Criteria
Dyspepsia Symptom Complex 1. Pain may be of a burning quality but without a retrosternal
component
Pattern and Heterogeneity 2. Pain is commonly induced or relieved by ingestion of a meal
but may occur while fasting
The dyspepsia symptom complex is broader than the 4 cardi- 3. Postprandial distress syndrome may coexist
nal symptoms that constitute the Rome III definition and
includes multiple symptoms such as epigastric pain, bloating, *According to the Rome III Consensus Committee.
†
Criteria must be fulfilled for the previous 3 months with symptom onset at
early satiation, fullness, epigastric burning, belching, nausea, least 6 months prior to diagnosis.
and vomiting. Although often chronic, symptoms in func- Adapted from Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal
tional dyspepsia are mostly intermittent, even during highly disorders. In: Drossman DA, Corazziari E, Delvaux M, et al, editors. Rome III.
symptomatic periods.3,16 In persons with functional dyspepsia The functional gastrointestinal disorders. 3rd ed. McLean, Va.: Degnon
Associates; 2006; pp 427-428.
who present for tertiary care, the most frequent symptoms are
postprandial fullness and bloating, followed by epigastric
pain, early satiation, nausea, and belching.3,17-20 There is con- a homogeneous (i.e., unidimensional) condition.22-24 These
siderable heterogeneity, as demonstrated, for example, by the studies have confirmed the heterogeneity of the dyspepsia
number of symptoms patients report (Fig. 14-1). In the general symptom complex but have not provided a clinically mean-
population, the most frequent dyspeptic symptoms are post- ingful classification of the syndrome.
prandial fullness, early satiation, upper abdominal pain, and Several attempts have been made to identify clinically
nausea.21-23 meaningful subgroups of persons with dyspepsia to attempt
Weight loss is traditionally considered an “alarm” to simplify the intricate heterogeneity of the dyspepsia
symptom, pointing to potentially serious organic disease. symptom complex and guide management. The Rome II com-
Studies in tertiary care patients with functional dyspepsia mittee proposed a classification based on a predominant
have also shown a high frequency of unexplained weight symptom of pain or discomfort. Although correlations were
loss,17,18 and population-based studies in Australia and Europe found between this classification and the presence or absence
have shown an association between uninvestigated dyspepsia of Hp infection, absence or presence of delayed gastric empty-
and unexplained weight loss.22,23 ing, and response or lack of response to acid-suppressive
therapy,25,26 the classification has been criticized because of the
difficulty in distinguishing pain from discomfort, lack of a
Subgroups widely accepted definition of “predominant,” uncertainty
The heterogeneity of the dyspepsia symptom complex is well about overlap between the symptom subgroups, lack of an
accepted. Factor analysis of dyspepsia symptoms in the association with putative pathophysiologic mechanisms, and
general population and tertiary care patients with functional especially lack of stability of the predominant symptom over
dyspepsia have not suggested that functional dyspepsia is short time periods.5,27-30
100
90
80
Frequency (%) 70
60
50
40
Absent
Mild
30 Moderate
Severe
20
10
0
Fullness Bloating Pain Nausea Early Belching Epigastric Vomiting
satiety burning
FIGURE 14-1. Frequency of symptoms (percent of patients) and their severity ratings in 674 patients with functional dyspepsia seen at
a tertiary referral center. (Unpublished, University of Gasthuisberg, Leuven, Belgium.)
A number of population-based studies have evaluated the

Uninvestigated dyspepsia
(postprandial fullness, early satiation, Rome III–based classification of functional dyspepsia into EPS
epigastric pain, epigastric burning) and PDS. In 2 European studies from Sweden and Italy, evalu-
ation of study subjects included upper GI endoscopy with
Endoscopy, other mucosal biopsies, and functional dyspepsia was found in 11%
investigations to 15% of the adult population. Both EPS and PDS were readily
identifiable, and the frequency of overlap between the 2 was
lower than expected.33,34 A population-based questionnaire
study from the United States also confirmed good separation
Functional Organic dyspepsia
dyspepsia (e.g., ulcer, esophagitis)
between EPS and PDS symptom patterns.35 Results of these
epidemiologic studies from different parts of the world
support the Rome III classification of EPS and PDS based on
a better-than-expected separation of the subgroups in the
general population. By contrast, studies in patients referred to
Postprandial distress Epigastric pain a gastroenterologist for consultation for functional dyspepsia
syndrome: syndrome: have shown much poorer separation between PDS and EPS.36
Meal-related FD Meal-unrelated FD A post hoc analysis of an open-access endoscopy-based study
Early satiation Epigastric pain conducted prior to the publication of the Rome III criteria
Postprandial fullness Epigastric burning found considerable overlap between the 2 subsets and a large
group of dyspeptic patients who could not be classified into 1
FIGURE 14-2. Classification of uninvestigated dyspepsia, functional of the 2 groups.37
dyspepsia (FD), and subtypes of functional dyspepsia, according The validity of the Rome III classification will have to be
to the Rome III criteria. assessed in additional ongoing and future studies. In a pro-
spective study of 3014 patients attending a gastroenterology
outpatient clinic in Taiwan, a diagnosis of functional dyspep-
sia was made in 20.2%, of whom 63% had EPS and 63% had
The Rome III Consensus Committee proposed a different PDS, including 26% with an overlap of the 2 types of func-
classification (Fig. 14-2). Studies in patients with functional tional dyspepsia.38 Therefore, in patients seen in outpatient
dyspepsia seen at a tertiary care center and persons with clinics or referred for endoscopy, both self-reported meal-
uninvestigated dyspepsia in the general population have related symptoms and epigastric pain often coexist. Conceiv-
revealed that between 40% and 75% of dyspeptic persons ably, incorporating an assessment of the severity and timing
report aggravation of symptoms after ingestion of a meal.23,31,32 (e.g., postprandial only) of discomfort may reduce the fre-
Assuming a distinction between meal-related and meal- quency of overlap.
unrelated symptoms might be pathophysiologically and clini-
cally relevant, the Rome III Consensus Committee proposed
that functional dyspepsia be used as an umbrella term and that Overlap with Heartburn and IBS
postprandial distress syndrome (PDS)—characterized by meal- Although early investigators considered a group of patients
related dyspeptic symptoms, postprandial fullness, and early with reflux-like dyspepsia,4 the Rome committees did not con-
satiation—be distinguished from epigastric pain syndrome sider heartburn to arise primarily from the gastroduodenal
(EPS), characterized by meal-unrelated dyspeptic symptoms, region, and this symptom was excluded from the definition of
epigastric pain, and epigastric burning.5 dyspepsia.2,5 Heartburn commonly occurs with dyspeptic
symptoms, both in the general population and in persons with define functional dyspepsia according to the Rome I and II
functional dyspepsia,23,27,39,40 but distinguishing GERD from consensus definitions.
dyspepsia is hampered by a number of confounding factors
like the presence of dyspepsia-type symptoms in many
patients with GERD23,41 and difficulties in recognizing heart- Delayed Gastric Emptying
burn by patients and physicians.42,43 Several studies have investigated gastric emptying and its
The Rome II Consensus Committee stated that patients relationship to the pattern and severity of symptoms in
with typical heartburn as a dominant complaint almost invari- patients with functional dyspepsia. The frequency of delayed
ably have GERD and should be distinguished from patients gastric emptying ranges from 20% to 50%.3,5 In a meta-analysis
with dyspepsia.2 Although this distinction is probably valid, of 17 studies involving 868 dyspeptic patients and 397 con-
it has become clear that the predominant symptom approach trols, a significant delay in solid gastric emptying was present
does not reliably identify or exclude patients with GERD.44,45 in almost 40% of patients with functional dyspepsia.54 Most of
The Rome III Consensus Committee has proposed identifying the studies, however, were performed in small groups of
patients with frequent heartburn and using a word-picture patients. In the largest studies, gastric emptying of solids was
questionnaire to facilitate patients’ recognition of heartburn. delayed in about 30% of the patients with functional dyspep-
Such an approach may identify patients with functional sia.3,5,20,55,56 Most studies failed to find a convincing relationship
dyspepsia who will respond to acid-suppressive therapy or in between delayed gastric emptying and the pattern of symp-
whom pathologic esophageal acid exposure can be demon- toms. Three large-scale single-center studies from Europe
strated.44,45 Whereas the Rome II definition of functional showed that patients with delayed gastric emptying for solids
dyspepsia excluded patients in whom heartburn was the pre- are more likely to report postprandial fullness, nausea, and
dominant symptom and was unclear about those in whom vomiting,20,55,56 although 2 other large multicenter studies in
heartburn was not the predominant symptom, the Rome III the United States found no or a weak association.57,58 Whether
definition states that heartburn is not a gastroduodenal delayed gastric emptying causes symptoms or is an epiphe-
symptom, although it often occurs in association with symp- nomenon is a matter of ongoing controversy.
toms of functional dyspepsia, and its presence does not
exclude a diagnosis of functional dyspepsia.5 Similarly, the
frequent co-occurrence of functional dyspepsia and irritable Impaired Gastric Accommodation to a Meal
bowel syndrome (IBS)46 is explicitly recognized in the Rome The motor functions of the proximal and distal stomach differ
III consensus guidelines but does not exclude a diagnosis of remarkably. Whereas the distal stomach regulates gastric
functional dyspepsia.5 empting of solids by grinding and sieving the content until
the particles are small enough to pass through the pylorus, the
proximal stomach serves mainly as a reservoir during and
Epidemiology after ingestion of a meal. Accommodation of the stomach to a
Dyspeptic symptoms are common in the general population, meal results from vagally mediated reflex relaxation of the
with frequencies ranging from 10% to 45%.11,16,23,27,47,48 The fre- proximal stomach, thereby enabling the stomach to handle
quency of dyspepsia is slightly higher in women than men, large intragastric volumes without a rise in intragastric pres-
and the influence of age varies among studies. Results of prev- sure.59 Studies using intragastric manometry have shown that
alence studies are strongly influenced by the criteria used to ingestion of a meal is associated with a drop in intragastric
define dyspepsia, and several studies have included patients pressure followed by gradual recovery of the pressure during
with typical symptoms of GERD or have not taken into account continued ingestion of nutrients, with increasing meal-induced
the presence of dyspepsia-type symptoms in many patients satiation.60
with GERD. When heartburn is excluded, the frequency of Studies using a gastric barostat, scintigraphy, US single
uninvestigated dyspepsia in the general population ranges photon emission CT (SPECT), or noninvasive surrogate
from 5% to 15%.16,23,47,48 Long-term follow-up studies have sug- markers (satiation drinking test) have all identified impaired
gested improvement in or resolution of symptoms in more gastric accommodation in roughly 40% of patients with func-
than half of patients.16,47,49,50 The annual incidence of dyspepsia tional dyspepsia.3,5,17,19,59 Insufficient accommodation of the
has been estimated to range from 1% to 6%.16 proximal stomach during and after ingestion of a meal may
Quality of life is significantly affected by dyspepsia, espe- be accompanied by increased intragastric pressure and activa-
cially functional dyspepsia.50 Although the majority of patients tion of mechanoreceptors in the gastric wall, thus inducing
do not seek medical care, a substantial proportion of patients symptoms. Although a number of studies have found an asso-
will eventually seek consultation, which results in substantial ciation between impaired accommodation and early satiation
costs.16,50-53 Factors that influence health care seeking are or weight loss, others have failed to find such an associa-
symptom severity, fear of an underlying serious disease, psy- tion.3,5,17,59 The mechanisms by which impaired accommoda-
chological distress, and lack of adequate psychosocial support53 tion can cause symptoms is still unclear. Meal ingestion in
(see later). the absence of proper relaxation of the proximal stomach
may be accompanied by activation of tension-sensitive mecha-
noreceptors in the proximal stomach. On the other hand,
Pathophysiology insufficient accommodation of the proximal stomach may
Several pathophysiologic mechanisms have been suggested force the meal into the distal stomach, thereby causing activa-
to underlie functional dyspeptic symptoms: delayed gastric tion of tension-sensitive mechanoreceptors in a distended
emptying, impaired gastric accommodation to a meal, hyper- antrum.59
sensitivity to gastric distention, altered duodenal sensitivity to
lipids or acid, abnormal intestinal motility, and central nervous
system dysfunction.3 The heterogeneity of functional dyspep- Hypersensitivity to Gastric Distension
sia seems to be confirmed by the contribution of 1 or more Visceral hypersensitivity, defined as abnormally enhanced per-
of these disturbances in subgroups of patients. Studies that ception of visceral stimuli, is considered 1 of the major patho-
investigated the pathophysiologic mechanisms of functional physiologic mechanisms of all functional GI disorders.60
dyspepsia predated the Rome III classification, so most studies Several studies have established that, as a group, patients with
functional dyspepsia are hypersensitive to isobaric gastric dis-

tention.3,5,18 The level at which visceral hypersensitivity is gen- Infection
erated is unclear, and there is evidence for involvement of
tension-sensitive mechanoreceptors as well as alterations at Hp Infection
the level of visceral afferent nerves and the central nervous Depending on the region and population studied, a variable
system.61-64 proportion of patients with functional dyspepsia are infected
with Hp.3,5 Although this organism is associated with a
number of organic causes of dyspepsia, there is only limited
Altered Duodenal Sensitivity to Lipids or Acid evidence to support a causal relationship between Hp and
In healthy persons and patients with functional dyspepsia, functional dyspepsia.78 No consistent differences in symptom
duodenal perfusion with nutrient lipids, but not glucose, pattern or putative pathophysiologic mechanisms have been
enhances the perception of gastric distention through a mech- found between Hp–positive and Hp–negative subjects.3,5,79
anism that requires lipid digestion and the subsequent release The best evidence in support of a role for Hp in the pathogen-
of cholecystokinin.65-67 Duodenal infusion of hydrochloric acid esis of functional dyspepsia is the small but statistically
induces nausea in patients with functional dyspepsia but not significant beneficial effect of eradication therapy on symp-
in healthy subjects, suggesting duodenal hypersensitivity to toms in patients with functional dyspepsia (see later and
acid.68 Duodenal pH monitoring with a clipped pH electrode Chapter 51).79,80
has revealed increased postprandial duodenal acid exposure
in patients with functional dyspepsia compared with controls,
and this difference has been attributed to impaired clearance Postinfection Functional Dyspepsia
of acid from the duodenum.69 On the basis of these observa- Postinfection functional dyspepsia was first proposed as a
tions, increased duodenal sensitivity to lipids or acid has been possible clinical entity on the basis of a large retrospective
proposed to contribute to the generation of symptoms in study from a tertiary referral center.19 Compared with patients
patients with functional dyspepsia, but further research in this who had functional dyspepsia of unspecified onset, patients
area is needed. with a history suggestive of postinfection functional dyspep-
sia were more likely to report symptoms of early satiation,
weight loss, nausea, and vomiting and had a significantly
Other Mechanisms higher frequency of impaired accommodation of the proximal
One study of patients with functional dyspepsia reported a stomach, which was attributed to dysfunction at the level of
high frequency of rapid gastric emptying that was correlated gastric nitrergic neurons.19 In a prospective cohort study, func-
with postprandial symptom intensity,70 but other studies have tional dyspepsia was increased 5-fold in patients 1 year after
failed to support the findings.20,32 Phasic fundic contractions acute Salmonella gastroenteritis, compared with subjects who
induce transient increases in gastric wall tension that can be had not had gastroenteritis.81 Additional studies are required
perceived in patients with functional dyspepsia.62 One study to identify the underlying pathophysiology and risk factors
reported lack of suppression of phasic contractility of the and to assess the long-term prognosis.
proximal stomach after a meal in a subset of patients with
functional dyspepsia.71 Abnormalities in the control of gastric
myoelectrical activity (measured by cutaneous electrogastrog- Psychosocial Factors
raphy) have been found in up to two thirds of patients with A review of the literature reveals a clear association between
functional dyspepsia.72,73 No correlation was found between psychosocial factors and functional dyspepsia.3,5,82 The most
the symptom pattern and the presence of electrogastrographic common psychiatric comorbidities in patients with functional
findings. Small bowel motor alterations, most commonly dyspepsia are anxiety, depressive or somatoform disorders,
hypermotility with burst activity or clusters and an increased and a recent or remote history of physical or sexual abuse.
proportion of duodenal retrograde contractions (see Chapter Psychological distress has long been a recognized feature of
99), have been reported in patients with functional dyspepsia, health care–seeking behavior in patients with functional bowel
but no clear correlation with symptoms has been found.74 disorders, including functional dyspepsia. Studies have con-
firmed an association between dyspeptic symptoms in the
general population and psychosocial factors like somatization,
Pathogenic Factors anxiety, and stressful life events; this association argues against
The cause of symptoms in patients with functional dyspepsia a mere health care–seeking effect.31,82,83 Symptom severity in
has not been established, but evidence exists for genetic sus- patients with functional dyspepsia seen at a tertiary care
ceptibility, infectious factors, and psychological factors. The center is more strongly related to psychosocial factors (espe-
relationship between potential pathogenic factors and puta- cially depression, abuse history, and somatization) than to
tive pathophysiologic mechanisms has not been addressed in abnormalities of gastric sensorimotor function.84
depth. Although these observations show a close interaction
between different psychosocial variables and the presence and
severity of symptoms of functional dyspepsia, they do not
Genetic Predisposition establish whether psychosocial factors and functional dyspep-
Population studies have suggested that genetic factors con- sia are separate manifestations of a common predisposition or
tribute to functional dyspepsia. The frequency of dyspepsia in whether psychosocial factors play a causal role in the patho-
first-degree relatives of affected patients is increased com- physiology of dyspeptic symptoms. The relationship is
pared with the frequency in their spouses.75 Polymorphisms unlikely to be simple. A factor analysis of symptoms of func-
of the G-protein beta polypeptide 3 (GNB3) gene have been tional dyspepsia and their relationship with pathophysiology
associated with the risk of functional dyspepsia76; the specific and psychopathology has demonstrated the heterogeneity
polymorphism and an association with dyspepsia subgroups and complexity of these interactions.24 The factor analysis
have been inconsistent in studies from different parts of identified 4 separate functional dyspepsia symptom factors,
the world.77 Additional and larger confirmatory studies are of which the factor consisting of epigastric pain was asso
needed. ciated with visceral hypersensitivity, several psychosocial
dimensions (including somatization and neuroticism), and with dyspepsia (especially NSAIDs) should be discontinued
low health-related quality of life.24 if possible. In patients in whom NSAIDs cannot be discontin-
These observations suggest a relationship between psy- ued, a trial of a PPI can be considered, although many guide-
chosocial factors and visceral hypersensitivity in particular. lines recommend endoscopic evaluation first to exclude peptic
Acutely induced anxiety in healthy volunteers, however, was ulcer (see later).
not associated with increased visceral sensitivity but with
decreased gastric compliance and a significant inhibition of
meal-induced accommodation.85 In patients with functional
Laboratory Testing
dyspepsia, a correlation between anxiety and gastric sensitiv- The cost-effectiveness of routine laboratory testing, especially
ity was found in the subgroup of hypersensitive patients but in younger patients with uncomplicated dyspepsia, has not
not in the group as a whole.86 A history of physical or sexual been established. Nevertheless, most clinicians will consider
abuse was associated with visceral hypersensitivity in patients routine tests (complete blood count, serum electrolytes,
with functional dyspepsia.87 Clearly the role of psychosocial calcium, liver biochemical tests, and thyroid function) after the
factors in the generation and severity of symptoms, especially age of 45 to 55. Other studies like a serum amylase level, anti-
in terms of their impact on clinical management, merits further bodies for celiac disease, stool testing for ova and parasites
study. and for Giardia antigen, and a pregnancy test may be consid-
ered in selected cases.
APPROACH TO UNINVESTIGATED
Initial Management Strategies
DYSPEPSIA
In most cases, the patient’s history and physical examination
Taking into account the high prevalence of dyspepsia and the will allow dyspepsia to be distinguished from symptoms sug-
large number of persons who present to a physician for their gestive of esophageal, pancreatic, or biliary disease, but both
symptoms, the initial aim of management is to decide which primary care physicians and gastroenterologists should be
patients can be treated empirically and which patients should aware that the patient’s history and physical findings, and
be referred for additional diagnostic evaluation. even the presence of alarm symptoms, are unreliable in distin-
guishing functional from organic causes of dyspepsia.6,9,10,88,89
Therefore, most guidelines and recommendations advocate
History and Physical Examination prompt endoscopy when risk factors for an organic cause of
A complete clinical history should be obtained and a physical dyspepsia (e.g., NSAID use, age at least 45 to 55, alarm symp-
examination performed in all patients with dyspepsia. The toms) are present.90-92 The optimal management strategy for
nature, frequency, and chronicity of the symptoms, as well the majority of patients who do not have a risk factor for an
as their relationship to meals and the possible influence of organic cause of dyspepsia remains a matter of debate and
specific dietary factors, should be assessed. The onset of controversy; several approaches have been proposed. Avail-
symptoms—acute with a gastroenteritis-like episode or more able options include (1) prompt diagnostic endoscopy fol-
gradual—is also of interest. The presence and degree of weight lowed by targeted medical therapy; (2) noninvasive testing for
loss, if present, must be determined, as should other alarm Hp infection, followed by treatment based on the result (“test-
symptoms like blood loss and dysphagia, as well as anemia. and-treat” strategy); and (3) empirical antisecretory drug
Distinguishing the EPS from the PDS symptom subgroup therapy. In the 2 latter strategies, endoscopy is performed in
according to the Rome III classification may influence the patients who do not respond to treatment or experience recur-
choice of treatment (see later). In patients with long-standing rent symptoms after treatment. In theory, empirical therapy
symptoms, the reason for seeking health care at this time with a prokinetic agent could also be considered as an initial
should be elicited so specific fears and concerns can be option but is generally not recommended because of the
addressed. Assessment of symptoms or signs of a systemic lack of widely available prokinetic drugs with established
disorder (e.g., diabetes mellitus, cardiac disease, thyroid dis- efficacy.
orders) and of the patient’s family and personal history will
indicate whether the patient is at risk for a particular organic
disease that may present as dyspepsia. Physical findings such Prompt Endoscopy and Directed Treatment
as an abdominal mass, organomegaly, ascites, or a positive Diagnostic upper GI endoscopy allows direct detection of
fecal occult blood test result warrant further evaluation. organic causes of dyspepsia, such as peptic ulcer, erosive
Specific attention should be given to a history of heartburn, esophagitis, or malignancy. Endoscopy before any therapy has
and a word-picture questionnaire may help the patient recog- been initiated is still considered the gold standard for diagnos-
nize the typical symptom pattern.43 Burning pain confined to ing upper GI disorders.93 The procedure may also have a reas-
the epigastrium is a cardinal symptom of dyspepsia and not suring effect on patients and physicians.94-96 Gastric mucosal
considered heartburn unless it radiates retrosternally. The biopsies facilitate diagnosis of Hp infection, which should be
presence of frequent and typical reflux symptoms should lead followed by eradication therapy if results are positive. Endos-
to a provisional diagnosis of GERD rather than dyspepsia, and copy has been claimed to detect gastric cancer at an early
the patient should be treated initially for GERD (see Chapter curable stage, but detecting early gastric cancer in a symptom-
44). Overlap of GERD with dyspepsia is probably frequent atic person is a relatively rare occurrence, and evidence for the
(see earlier) and should be considered if the patient’s symp- claim is weak at best.97-99
toms do not respond to appropriate management of GERD. On the other hand, endoscopy is expensive and invasive
The possible presence of overlapping IBS should also be and may not have such a major impact on treatment after all.
assessed, and symptoms that improve with bowel movements Patients found to have peptic ulcer or erosive esophagitis will
or are associated with changes in stool frequency or consis- receive antisecretory drug therapy, and in those with a nega-
tency should lead to a presumptive diagnosis of IBS. tive upper endoscopy result, functional dyspepsia and noner-
Use of prescription and nonprescription medications is osive GERD are likely diagnoses, both of which can be treated
particularly important, and medications commonly associated empirically with antisecretory drug therapy. Still, it has been
argued that initial empirical antisecretory drug therapy will Randomized placebo-controlled trials have shown only
only delay endoscopy, because both functional dyspepsia and a modest reduction in symptoms of dyspepsia after a test-and-
GERD are likely to recur after discontinuation of empirical treat approach in primary care.110-112 A meta-analysis of studies
therapy, at which time the patient will be referred for comparing a test-and-treat strategy with empirical antisecre-
endoscopy. tory drug therapy of dyspepsia found little difference in the
A number of randomized controlled trials have compared frequency of symptom resolution or costs between the 2
prompt endoscopy with an empirical noninvasive manage- approaches.113 Although earlier models that assumed higher
ment strategy. A meta-analysis of 5 trials that compared initial prevalences of Hp suggested great benefit to a test-and-treat
endoscopy with a test-and-treat strategy concluded that initial strategy,114-116 economic models have suggested that compared
endoscopy may be associated with a small reduction in the with empirical antisecretory drug therapy, the test-and-treat
risk of recurrent dyspeptic symptoms but that this gain is not approach may be equally or less cost-effective.117,118 The test-
cost-effective.100 Most relevant studies have found that the and-treat strategy as an initial approach to uninvestigated
direct and indirect costs associated with prompt endoscopy dyspepsia is most likely to be beneficial in areas where the
are higher than those associated with empirical therapy, and Hp infection rate is high.
the costs are not completely offset by reduced medication use
or subsequent physician visits.101-103 Available data, therefore,
do not support early endoscopy as a cost-effective initial Empirical Antisecretory Drug Therapy
management strategy for all patients with uncomplicated Initial empirical antisecretory drug therapy is widely used
dyspepsia. in primary care for patients with uninvestigated dyspepsia.
Nevertheless, most relevant practice guidelines advocate This approach is attractive because it controls symptoms
initial endoscopy in all patients above a certain age threshold and heals lesions in most patients with underlying GERD or
(usually age 45 to 55) to detect a potentially curable upper GI PUD and may be beneficial in up to one third of patients with
malignancy.90-92 The rationale is that the vast majority of gastric functional dyspepsia.119,120 PPIs provide superior symptom
malignancies occur in patients older than 45, and the rate of relief compared with H2RAs, and the response usually occurs
cancer detection rises in persons with dyspepsia who are 45 within 2 weeks of therapy.101 Disadvantages of empirical PPI
or older.97-99 Most patients with newly diagnosed gastric cancer therapy are rapid symptomatic relapse after cessation of
are already incurable at the time of diagnosis, however, and therapy and the potential for rebound gastric hypersecre-
many will have an alarm feature that would have warranted tion,121 so many patients require long-term PPI therapy. As
immediate endoscopy.99 In patients younger than age 45 who noted earlier, a meta-analysis of studies that compared a test-
have a family history of gastric cancer, emigrated from a and-treat approach with empirical antisecretory drug therapy
country with a high rate of gastric cancer, or have had a partial in dyspepsia found little difference in symptom resolution or
gastrectomy, early endoscopy is also recommended. costs between the 2 strategies113; however, economic analyses
indicate that empirical antisecretory drug therapy may be
equally or more cost-effective.117,118
Test and Treat for Hp Infection
Hp is causally associated with the majority of peptic ulcers
and is the most important risk factor for gastric cancer104 (see Recommendations
Chapters 51, 53, and 54). Because of the involvement of Hp in The optimal cost-effective approach to initial management of
PUD several consensus panels have advocated noninvasive uncomplicated dyspepsia remains unclear. Clinical decisions
testing for Hp in young patients (<45 to 55 years of age) with should take into account specific aspects of a patient’s case and
uncomplicated dyspepsia. Patients with a positive test result weigh several risk-benefit factors. In a young dyspeptic patient
should receive eradication therapy (see Chapter 51), whereas (<age 45 to 55) without alarm features, initial endoscopy
patients with a negative test result should be treated empiri- cannot be recommended because the yield is low and the test
cally, usually with a PPI. The benefits of this test-and-treat is unlikely to lead to improved outcomes. This position can be
strategy are the cure of PUD or prevention of future peptic reconsidered if the patient is worried about an underlying
ulcers and symptom resolution (≈7% above the rate with disease, has a family history of cancer, or has emigrated from
placebo) in a small subset of patients with functional dyspep- an area with a high incidence of gastric or esophageal cancer.
sia who are infected with Hp.80,105 Eradication of Hp eliminates In a population with a high prevalence (>20%) of Hp infection,
chronic gastritis and in theory may contribute to a reduction the test-and-treat approach remains attractive because patients
in the risk of Hp–associated gastric cancer.106 with PUD will be cured. Tests of choice are the urea breath
On the other hand, in Western countries, the prevalence of test or the fecal antigen test for Hp. Hp–positive patients
Hp infection in patients with uninvestigated dyspepsia is should be given a 7- to 14-day course of Hp eradication
declining rapidly, and infection rates are especially low (10% therapy (see Chapter 51). In those who are Hp–negative, a PPI
to 30%) in persons younger than age 30. Widespread antibiotic can be prescribed for 1 to 2 months. In populations where the
use has the disadvantage of inducing resistance and occasion- prevalence of Hp infection is low, empirical antisecretory drug
ally causing a drug allergy. Whether eradication of Hp causes therapy (PPI for 1 to 2 months) appears to be the preferred
or worsens GERD has long been debated,107 but a 2013 ran- option. Patients who fail to respond to these initial approaches,
domized controlled eradication trial in Hp–positive patients and possibly those in whom symptoms recur after cessation
with GERD failed to demonstrate any worsening of GERD.108 of antisecretory drug therapy, should undergo endoscopy,
Furthermore, the accuracy of noninvasive testing depends on although the yield is likely to be low.
both the prevalence of Hp in the population and the sensitivity In patients older than age 45 to 55 without alarm features,
and specificity of the test. Serologic tests for Hp are the least most guidelines recommend initial diagnostic endoscopy,
expensive but also the least accurate. If the prevalence of Hp although a benefit in the detection of early-stage malignancies
in a population is less than 60%, the fecal antigen test and urea remains unproved. In these cases, management will depend
breath test for Hp are preferred; their higher accuracy reduces on the endoscopic findings and detection of Hp, but PPI
inappropriate treatment of patients without Hp infection (see therapy is likely to be prescribed to the majority of these
Chapter 51).109 patients.
Additional Investigations randomized placebo-controlled trials that evaluated the effi-

cacy of H2RAs in patients with functional dyspepsia reported
Additional investigations may be pursued in patients with a significant benefit over placebo, with a relative risk reduc-
progressive or refractory symptoms that do not respond to tion of 23% and a number needed to treat of 7.125 H2RAs thus
initial management. Testing for celiac disease and Giardia appear to be efficacious in functional dyspepsia, but many of
infection is useful for patients with refractory symptoms, these trials probably included patients with GERD under a
especially when accompanied by weight loss. In patients with broad interpretation of functional dyspepsia, thereby account-
severe pain or weight loss, abdominal US or CT can be used ing for much of the benefit.
to rule out pancreaticobiliary disease and screen for mesen- A meta-analysis of 10 placebo-controlled randomized
teric ischemia. trials of PPIs for functional dyspepsia also confirmed that this
In cases of severe postprandial fullness, and especially in class of agents was superior to placebo, with a number needed
cases of refractory nausea and vomiting, a gastric emptying to treat of 10 (Table 14-1).125,126 The relative risk reduction
test using scintigraphy or a breath test can be considered (see (13%) was lower than for H2RAs, probably reflecting more
Chapter 43). When a severe delay in gastric emptying is stringent entry criteria and better exclusion of patients with
detected, a small bowel x-ray can rule out mechanical obstruc- GERD. No difference in efficacy was found between half-dose
tion as a contributing factor. In cases of refractory intermittent and full-dose PPI therapy, and double-dose PPI therapy was
epigastric pain or burning, esophageal pH with impedance not superior to single-dose therapy. The patient’s Hp status
monitoring is useful for diagnosing atypical manifestations of did not affect the response to PPI therapy. Subgrouping of
GERD not responding sufficiently to empirical antisecretory functional dyspepsia using previous Rome classifications
drug therapy. Psychological or psychiatric assessment is rec- showed a trend for PPI therapy to be most effective in the
ommended for patients with long-standing refractory or group with overlapping reflux, less effective in the group with
debilitating symptoms. Electrogastrography, barostat studies, epigastric pain, and lacking a statistically significant effect in
or simple nutrient challenge tests have been used as research the group with dysmotility.126
tools but have no established role in the clinical management
of patients with dyspepsia.
Eradication of Hp Infection
A Cochrane meta-analysis reported a 10% pooled relative-risk
TREATMENT OF FUNCTIONAL DYSPEPSIA reduction in dyspepsia for therapy to eradicate Hp infection
compared with placebo at 12 months of follow-up, with a
number to treat of 14 (Table 14-2).80 Arguments against eradi-
General Measures cation therapy are the low number of responders and the
Reassurance and education are of primary importance in delayed occurrence of a demonstrable symptomatic benefit.
patients with functional dyspepsia. In spite of normal findings On the other hand, Hp eradication can induce sustained
at endoscopy, the patient should be given a confident and remission of dyspepsia, albeit in a small minority of patients.127
positive diagnosis. In patients with IBS, a positive physician- Other arguments in favor of eradication therapy are protection
patient interaction has been shown to reduce health care– against peptic ulcer, presumed protection against gastric
seeking behavior, and this approach is probably applicable to cancer, and the short duration and relatively low cost of
patients with functional dyspepsia as well.122 treatment.
Lifestyle and dietary measures are usually prescribed to
patients with functional dyspepsia, but the impact of dietary
interventions has not been studied systematically.11 Having Prokinetic Agents
patients eat smaller, more frequent meals seems logical. Gastric prokinetic agents are a heterogeneous class of com-
Because the presence of lipids in the duodenum enhances pounds that act through different types of receptors. The effi-
gastric sensitivity, avoiding meals with a high fat content may cacy of available prokinetic agents in patients with functional
be advisable.65,66 Similarly, consumption of spicy foods con- dyspepsia has been controversial.125,128,129 A meta-analysis
taining capsaicin and other irritants is often discouraged.15 based mainly on studies of domperidone and cisapride sug-
Coffee may aggravate symptoms in some cases123 and, if gested that prokinetic agents were superior to placebo, with a
implicated, should be avoided. Cessation of smoking and con- relative risk reduction of 33% and a number needed to treat
sumption of alcohol are thought to be helpful, but with no of 6125; separate analyses also suggested efficacy.128 Metoclo-
convincing evidence of efficacy.124 Avoidance of aspirin and pramide and domperidone are dopamine receptor agonists
other NSAIDs is commonly recommended and seems sensi- with a stimulatory effect on upper GI motility. Unlike meto-
ble, although not of established value.14,15 If the patient has an clopramide, which may cause serious neurologic adverse
apparent coexisting anxiety disorder or depression, appropri- effects, domperidone does not cross the blood-brain barrier
ate treatment should be prescribed (see later). but has been associated with QT interval prolongation on
electrocardiography and may precipitate cardiac arrhythmias.
Cisapride facilitates acetylcholine release in the myenteric
Pharmacologic Treatment plexus via 5-hydroxytryptamine 4 (5-HT4) receptor agonism
For many but not all patients, pharmacotherapy will be con- and accelerates gastric emptying. The published trials of these
sidered. The efficacy of pharmacologic treatments for func- drugs have generally been of poor quality, and concerns have
tional dyspepsia is limited, however. been raised about publication bias. Moreover, cisapride has
been withdrawn from the market in the United States and
elsewhere for safety reasons.125
Acid-Suppressive Drugs Unfortunately, studies of other prokinetic agents have
In patients with GERD, a trial of antisecretory drug therapy generally failed to provide convincing evidence of symptom
often has both therapeutic and diagnostic value. Based on relief in patients with functional dyspepsia.129 The investi-
meta-analyses of therapeutic outcomes in patients with func- gated agents include the motilin receptor agonist ABT-229,
tional dyspepsia, the efficacy of antacids, sucralfate, and miso- the mixed 5-HT4 receptor agonist and 5-HT3 receptor anta
prostol has not been demonstrated.125 A meta-analysis of 12 gonist mosapride, the 5-HT4 receptor agonist tegaserod,
TABLE 14-1 Meta-analysis of 10 Randomized Controlled Trials* of PPI Therapy in Patients with Functional Dyspepsia
Relative Risk Relative Risk

Study/Year PPI n/N Placebo n/N 95% CI 95% CI
Blum 2000 274/395 171/203 0.82 [0.75, 0.90]
Bolling-Stemevald 2002 71/100 79/96 0.86 [0.74, 1.01]
Farup 1999 6/14 8/10 0.54 [0.27, 1.06]
Gerson 2005 16/21 9/19 1.61 [0.95, 2.74]
Peura 2004 (M96) 165/261 104/131 0.80 [0.70, 0.90]
Peura 2004 (M97) 164/249 109/133 0.80 [0.71, 0.91]
Talley 1998 (BOND) 242/423 81/110 0.78 [0.68, 0.89]
Talley 1998 (OPERA) 277/403 71/102 0.99 [0.85, 1.14]
van Zanten 2006 49/109 62/115 0.83 [0.64, 1.09]
Wong 2002 231/301 107/152 1.09 [0.97, 1.23]
Total (95% CI) 1495/2276 801/1071 0.87 [0.80, 0.96]
0.1 0.2 0.5 1 2 5 10

Favors PPI Favors placebo
*For each trial, n/N represents the proportion of nonresponders (n) over the total number of patients (N) in that group.
CI, confidence interval; PPI, proton pump inhibitor.
From Moayyedi P, Soo S, Deeks J, et al. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev 2011; CD001960.
and the dopamine D2 antagonist/acetylcholinesterase in in symptoms during treatment with mixed herbal prepara-
hibitor itopride.129 tions, Chinese herbals, or artichoke leaf extract.136-138 The
data suggest that some of these preparations are effective, but
the basis for this improvement remains to be determined.
Antidepressants One study reported that the chronic administration of red
Antidepressants are commonly used to treat functional GI pepper was more effective than placebo in decreasing the
disorders that do not initially respond to conventional intensity of dyspeptic symptoms in patients with functional
approaches. Although systematic reviews suggest that anxio- dyspepsia.139
lytics and antidepressants, especially tricyclic antidepressants,
may have some benefit in treating patients with functional GI
disorders, including functional dyspepsia (pooled relative risk New Drug Development
reduction of 45%), available trials are small and of poor quality, Fundic relaxants or visceral analgesics to reverse impaired
and publication bias cannot be excluded.130,131 The effects on gastric accommodation and visceral hypersensitivity are other
dyspepsia appear to be independent of the presence of depres- attractive targets of drug development for sensorimotor dis-
sion, and although antidepressants have been thought to orders of the upper GI tract. Although nitrates, sildenafil, and
decrease visceral sensitivity, no significant effects of antide- sumatriptan can relax the proximal stomach, they seem less
pressants on visceral sensitivity have been established in suitable for therapeutic application in functional dyspepsia. A
functional dyspepsia.132,133 The selective serotonin reuptake number of serotonergic drugs, including 5-HT1A receptor ago-
inhibitor (SSRI) paroxetine increased gastric accommodation nists, 5-HT3 receptor agonists, and 5-HT4 receptor agonists,
in healthy subjects,133 but clinical studies evaluating this can also enhance gastric accommodation.62,129 A small clinical
class of agents in patients with functional dyspepsia are trial with the 5-HT1A receptor agonist R137696 failed to show
lacking. A large controlled trial with the selective serotonin- any symptomatic benefit.129,140 By contrast, in a pilot trial the
norepinephrine reuptake inhibitor (SSNRI) venlafaxine failed 5-HT1A agonist buspirone, which is normally used to treat
to show any symptomatic benefit in patients with functional anxiety disorders and dose-dependently relaxes the stomach,
dyspepsia, and tolerance was poor.134 was shown to be superior to placebo in alleviating symptoms
of functional dyspepsia.141,142 Clinical benefit was also demon-
strated for the anxiolytic 5-HT1A agonist tandospirone in a
Other Pharmacotherapeutic Approaches multicenter controlled study in Japan.143 With both buspirone
On the basis of a meta-analysis of 4 trials, bismuth salts and tandospirone, improvement in anxiety or depression did
seemed efficacious, but the analysis had marginal statistical not correlate with improvement in dyspeptic symptoms. For
significance.125 Simethicone was superior to placebo in 1 con- buspirone, enhanced gastric accommodation is an underlying
trolled trial.135 Various studies have reported an improvement mechanism of action.142
TABLE 14-2 Meta-analysis of 17 Randomized Controlled Trials of Hp Eradication in Patients with Functional Dyspepsia
Treatment Relative Risk Relative Risk

Study/Year n/N Control n/N 95% CI 95% CI
Blum (OCAY) 1998 119/164 130/164 0.92 [0.81, 1.03]
Froehlich 2001 31/74 34/70 0.86 [0.60, 1.24]
Gisbert 2004 13/34 8/16 0.76 [0.40, 1.46]
Gonzalez Carro 2004 22/47 31/46 0.69 [0.48, 1.00]
Hsu 2001 34/81 36/80 0.93 [0.66, 1.33]
Koetz 2003 67/89 73/92 0.95 [0.81, 1.11]
Koskenpato 2003 61/77 63/74 0.93 [0.80, 1.08]
Malfertheiner 2003 338/534 177/266 0.95 [0.85, 1.06]
Martinek 2005 5/20 12/20 0.42 [0.18, 0.96]
Mazzoleni 2006 39/46 40/43 0.91 [0.79, 1.06]
McColl 1998 121/154 143/154 0.85 [0.77, 0.93]
Miwa 2000 33/48 28/37 0.91 [0.70, 1.18]
Ruiz 2005 46/79 64/79 0.72 [0.58, 0.89]
Talley (ORCHID) 1999 101/133 111/142 0.97 [0.85, 1.11]
Talley (USA) 1999 81/150 72/143 1.07 [0.86, 1.34]
van Zanten 2003 45/75 55/82 0.89 [0.70, 1.14]
Varannes 2001 74/129 86/124 0.83 [0.68, 1.00]
Total (95% CI) 1230/1934 1163/1632
0.1 0.2 0.5 1 2 5 10

Favors treatment Favors control
*For each trial, n/N represents the proportion of nonresponders (n) over the total number of patients (N) in that group.
CI, confidence interval.
From Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev 2011; CD002096.
Acotiamide (Z-338, YM443) is a novel compound that clinical benefit has not been established for agents in these
enhances release of acetylcholine via antagonism of the M1 classes.146
and M2 muscarinic receptors and also inhibits cholinesterase
activity. Several phase 2 studies in Europe, Japan, and the
United States evaluated acotiamide in patients with functional
Psychological Interventions
dyspepsia and established 100 mg 3 times a day as the optimal Although patients with functional dyspepsia have a higher
dose. These studies demonstrated the potential therapeutic prevalence of psychosocial comorbidities, the role of psycho-
benefit of acotiamide in alleviating postprandial fullness, early social factors in the generation of symptoms remains unclear.
satiation, and upper abdominal bloating.144 A 4-week phase 3 In part because of these psychosocial comorbidities, psycho-
placebo-controlled study in Japan confirmed the efficacy of logical interventions like group support with relaxation train-
acotiamide in patients with PDS,145 and the drug is now ing, cognitive therapy, psychotherapy, and hypnotherapy
approved in Japan for the treatment of functional dyspepsia have been used in patients with functional dyspepsia. A sys-
with symptoms of PDS. tematic review of clinical trials of psychological interventions
Visceral hypersensitivity is another attractive target for for functional dyspepsia found that all published trials claimed
drug development. The principal drug classes under evalua- benefit for psychological interventions, with effects persisting
tion are neurokinin receptor antagonists and peripherally for over 1 year, but all the studies were limited by inadequate
acting kappa opioid receptor agonists, but so far, convincing statistical analysis.147 The authors concluded that evidence to
Uninvestigated
Empirical therapy:
dyspepsia
“Test and treat”
PPI
Consider prokinetic
agent
No response
Endoscopy
70% 30%
Functional Organic dyspepsia

dyspepsia Peptic ulcer
Esophagitis
Eradicate if positive for Helicobacter Celiac disease
pylori and not already treated Giardiasis
Pancreatitis
Biliary disease
Others
Postprandial distress Epigastric pain

syndrome syndrome
Prokinetic agent Acid suppressive

Acotiamide* therapy
5-HT1A agonist
Prokinetic agent
Acid suppressive Acotiamide*
therapy 5-HT1A agonist
Antidepressant,
if symptoms refractory
FIGURE 14-3. An algorithm for management of patients with dyspepsia. Patients younger than age 45 to 55 who do not have alarm
features may be treated empirically, whereas all others should be evaluated initially by endoscopy. 5-HT, 5-hydroxytryptamine. *Not
available in USA.
confirm the efficacy of psychological interventions in func- profile (e.g., domperidone [or acotiamide where available])
tional dyspepsia is insufficient. can be considered (Fig. 14-3). Metoclopramide and, if avail-
able, cisapride should not be used because of the risk of serious
adverse events, and clinicians should be aware that domperi-
done has been associated with QT prolongation. Although, in
RECOMMENDATIONS theory, combinations of a PPI and prokinetic agent may have
additive symptomatic effects, therapy with a single drug is
In patients with functional dyspepsia who have mild or inter- preferable.
mittent symptoms, reassurance, education, and some dietary In patients with bothersome symptoms that persist despite
changes may suffice. Drug therapy may be considered in these initial therapies, a trial of a low-dose tricyclic antidepres-
patients with more severe symptoms or those who do not sant may be considered even in the absence of apparent
respond to reassurance and lifestyle changes. Testing for Hp anxiety or depression. Higher doses can be considered in inpa-
infection is recommended, and if the results are positive, erad- tients with significant anxiety or depression. SSNRIs should
ication therapy can be prescribed. An immediate impact on be avoided. A trial of simethicone, medically prescribed herbal
symptoms is unlikely, however, and any potential benefit is preparations with apparent benefit in controlled trials, or
observed mainly over a longer period of follow up. PPIs and bismuth salts may also be considered in refractory patients. In
prokinetic agents may be used as initial pharmacotherapy. case of debilitating epigastric pain, symptomatic analgesics—
The symptom pattern may help determine the most appropri- even possibly opioids—can be considered after appropriate
ate initial choice of therapy, and a change in drug class is exclusion of organic disease.
advisable in case the therapeutic response is insufficient. Referral to a psychiatrist or psychotherapist can be consid-
A 2- to (preferably) 4-week trial of PPI therapy should be ered in patients with obvious coexisting psychiatric disease, a
given to all patients with coexisting heartburn and to those history of physical or sexual abuse, or a debilitating impact of
with EPS. In case of symptomatic relief, treatment should be severe symptoms on daily life activities. Motivated patients
interrupted and intermittent or chronic therapy with a PPI (or may benefit from psychological approaches like psychother-
H2RA) tried in patients with repeated relapses. In those with apy, hypnotherapy, cognitive behavioral therapy, or relax-
PDS, a motility modifying drug with an attractive safety ation therapy.
Gastroenterology Surveillance Study (DIGEST). Scand J

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www.expertconsult.com. Cochrane Database Syst Rev 2011; CD002096.
90. Talley NJ, Vakil NB, Moayyedi P. American
3. Tack J, Bisschops R, Sarnelli G. Pathophysiology and Gastroenterological Association technical review on the
treatment of functional dyspepsia. Gastroenterology 2004; evaluation of dyspepsia. Gastroenterology 2005;
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CHAPTER

(postprandial fullness, early satiation, epigastric pain, epigas-

BOX 14-1 Causes of Dyspepsia

Luminal GI Tract Medications

Intolerance to Food or Drugs GERD

often accompanied by anorexia, rapid weight loss, or jaundice

A number of population-based studies have evaluated the

functional dyspepsia are hypersensitive to isobaric gastric dis-

Additional Investigations randomized placebo-controlled trials that evaluated the effi-

Relative Risk Relative Risk

Blum 2000 274/395 171/203 0.82 [0.75, 0.90]

Bolling-Stemevald 2002 71/100 79/96 0.86 [0.74, 1.01]

Farup 1999 6/14 8/10 0.54 [0.27, 1.06]

Gerson 2005 16/21 9/19 1.61 [0.95, 2.74]

Peura 2004 (M96) 165/261 104/131 0.80 [0.70, 0.90]

Peura 2004 (M97) 164/249 109/133 0.80 [0.71, 0.91]

Talley 1998 (BOND) 242/423 81/110 0.78 [0.68, 0.89]

Talley 1998 (OPERA) 277/403 71/102 0.99 [0.85, 1.14]

van Zanten 2006 49/109 62/115 0.83 [0.64, 1.09]

Wong 2002 231/301 107/152 1.09 [0.97, 1.23]

Total (95% CI) 1495/2276 801/1071 0.87 [0.80, 0.96]

0.1 0.2 0.5 1 2 5 10

Treatment Relative Risk Relative Risk

Blum (OCAY) 1998 119/164 130/164 0.92 [0.81, 1.03]

Froehlich 2001 31/74 34/70 0.86 [0.60, 1.24]

Gisbert 2004 13/34 8/16 0.76 [0.40, 1.46]

Gonzalez Carro 2004 22/47 31/46 0.69 [0.48, 1.00]

Hsu 2001 34/81 36/80 0.93 [0.66, 1.33]

Koetz 2003 67/89 73/92 0.95 [0.81, 1.11]

Koskenpato 2003 61/77 63/74 0.93 [0.80, 1.08]

Malfertheiner 2003 338/534 177/266 0.95 [0.85, 1.06]

Martinek 2005 5/20 12/20 0.42 [0.18, 0.96]

Mazzoleni 2006 39/46 40/43 0.91 [0.79, 1.06]

McColl 1998 121/154 143/154 0.85 [0.77, 0.93]

Miwa 2000 33/48 28/37 0.91 [0.70, 1.18]

Ruiz 2005 46/79 64/79 0.72 [0.58, 0.89]

Talley (ORCHID) 1999 101/133 111/142 0.97 [0.85, 1.11]

Talley (USA) 1999 81/150 72/143 1.07 [0.86, 1.34]

van Zanten 2003 45/75 55/82 0.89 [0.70, 1.14]

Varannes 2001 74/129 86/124 0.83 [0.68, 1.00]

Total (95% CI) 1230/1934 1163/1632

0.1 0.2 0.5 1 2 5 10

Functional Organic dyspepsia

Postprandial distress Epigastric pain

Prokinetic agent Acid suppressive

Gastroenterology Surveillance Study (DIGEST). Scand J

21. Tougas G, Chen Y, Hwang P, et al. Prevalence and impact

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