2.

patof dyspepsia

Pathophysiologic mechanisms and their relation to symptom pattern

Several pathophysiologic mechanisms have been suggested to underlie dyspeptic symptoms.

These include delayed gastric emptying, impaired gastric accommodation to a meal,
hypersensitivity to gastric distention, H. pylori infection, altered response to duodenal lipids or
acid, abnormal duodenojejunal motility, or central nervous system dysfunction (Figure 2). At
present, the pathophysiology of functional dyspepsia is only partially elucidated. However, there
is growing evidence that functional dyspepsia is in fact a very heterogeneous disorder and
different subgroups can be identified based on different demographic, clinical, and
pathophysiologic features.7, 8, 9, 10, 11

Figure 2

Normal fasting and postprandial gastric function; pathophysiologic mechanisms putatively

involved in functional dyspepsia.

View Large Image | Download PowerPoint Slide

Delayed gastric emptying

Delayed gastric emptying is traditionally considered a major pathophysiologic mechanism

underlying symptoms in functional dyspepsia and idiopathic gastroparesis.7, 11, 20, 21, 22, 23, 24, 25,
26, 27, 28, 29
Several studies have investigated the relationship between delayed gastric emptying
and symptom pattern and severity. Depending on the study, the percentage of dyspeptic patients
with delayed gastric emptying ranges from 20% to 50%.7, 11, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 In a
meta-analysis of 17 studies involving 868 dyspeptic patients and 397 controls, significant delay
of solid gastric emptying was present in almost 40% of patients with functional dyspepsia.23
However, most of the studies were performed in small groups of patients and small control
groups. In the largest studies, gastric emptying of solids was delayed in about 30% of the patients
with functional dyspepsia.7, 11, 27, 28, 29

Most studies failed to find a convincing relationship between delayed gastric emptying and
symptom pattern.20, 21, 22 More recently, 3 large-scale single-center studies showed that patients
with delayed gastric emptying for solids are more likely to report postprandial fullness, nausea,
and vomiting,7, 11, 28 although a large multicenter study failed to find any association29 (Table 2).
Almost all studies focused on solid emptying rate only. A recent large-scale study suggested an
association between delayed emptying for liquids and symptoms of postprandial fullness.11

Impaired gastric accommodation to a meal

The motor functions of the proximal and distal stomach differ remarkably. Whereas the distal
stomach regulates gastric emptying of solids by grinding and sieving the content until the
particles are small enough to pass the pylorus, the proximal stomach serves mainly as a reservoir.
Accommodation of the stomach to a meal consists of a relaxation of the proximal stomach,
providing the meal with a reservoir and enabling an increase in volume without an increase in
pressure.

Scintigraphic and ultrasonographic studies have shown an abnormal intragastric distribution of

food in patients with functional dyspepsia, with preferential accumulation in the distal
stomach.22, 30, 31, 32, 33 These findings suggest defective postprandial accommodation of the
proximal stomach. Consistently, studies using a gastric barostat have shown reduced proximal
gastric relaxation in response to a meal in patients with functional dyspepsia.8, 34 Insufficient
accommodation of the proximal stomach during and after the ingestion of a meal may be
accompanied by increased intragastric pressure and activation of mechanoreceptors in the gastric
wall, thus inducing symptoms.

Using a gastric barostat in 40 consecutive dyspeptic patients, we showed that impaired gastric
accommodation was present in 40% of the patients and that this impairment was associated with
symptoms of early satiety and weight loss.8 The relation between impaired gastric
accommodation and early satiety was also apparent from the correlation between the amplitude
of the meal-induced relaxation and the amount of calories ingested at maximum satiety in
patients with early satiety.8 Others, using single-photon emission computed tomography,
scintigraphy, or barostat studies of the proximal stomach, have confirmed the prevalence of
impaired accommodation in approximately 40% of dyspeptic patients, but the relationship with
symptom pattern has been found to be less consistent (Table 3).35, 36, 37

Table 3Prevalence of Impaired Accommodation and Relationship With Symptoms in Functional

Dyspepsia in Literature Studies
Prevalence of impaired
Study n Technique Correlation
accommodation (%)
Early satiety,
Tack et al., 19988 40 Barostat 40
weight loss
Single-photon emission
Kim et al., 200135 32 40 Weight lossa
computed tomography
Boeckxstaens et
44 Barostat 40 No correlation
al., 200236
Piessevaux et al.,
40 Scintigraphy 50 Early satiety
200337
View Table in HTML
aThe symptom of early satiety was not assessed in this study.

An unsolved issue is the site of symptom generation in patients with impaired accommodation.
When the proximal stomach is not relaxing properly, ingestion of a meal may be accompanied by
activation of tension mechanoreceptors in the proximal stomach wall and generation of
symptoms. On the other hand, insufficient accommodation of the proximal stomach may force
the meal into the distal stomach, thereby creating a distended antrum. Studies on the induction of
symptoms during proximal and distal gastric distention in humans have shown conflicting
results38, 39, 40 that are at least partly attributable to technical and methodological differences. The
gold standard for assessment of gastric sensitivity to distentions is currently the gastric barostat;
however, instead of dual barostat distentions, these studies used ultrasound measurements or
single water-filled or barostat balloons. In a recent study using a double gastric barostat
assembly, we showed that symptom profiles induced by gastric distention did not differ between
proximal and distal gastric distention and that mechanoreceptors from both sites may contribute
to symptoms.41 However, because the distal gastric wall is less compliant than the proximal
gastric wall, the distal stomach may produce greater symptoms in response to the same volume
of distention.41

Hypersensitivity to gastric distention

Physiologic stimuli during the digestive process are not normally perceived but in some
circumstances may induce conscious sensations. During the past decade, it has been suggested
that patients with functional gastrointestinal diseases may have a sensory dysfunction of the gut,
so that physiologic stimuli would induce symptoms.42 Several studies have clearly established
that, as a group, patients with functional dyspepsia have enhanced sensitivity to gastric
distention.9, 36, 43, 44, 45, 46 However, in these studies, different approaches to calculate sensitivity
to gastric distention and to determine the range of normality have been used.

A systematic analysis in a large group of controls and patients indicated that the increase in the
intra-balloon pressure over intra-abdominal pressure needed to induce discomfort or pain is the
most appropriate expression of sensitivity to gastric distention.9 According to that study, gastric
hypersensitivity was associated with symptoms of postprandial pain, belching, and weight loss.
So far, other, smaller-scale studies have failed to find an association between hypersensitivity
and symptom pattern (Table 4).36, 47

Table 4Prevalence of Hypersensitivity to Gastric Distention and Relationship With Symptoms

in Functional Dyspepsia in Literature Studies
Prevalence of hypersensitivity
Study n Correlation
(%)
Mertz et al., 199846 24 66 No correlation
47
Rhee et al., 2000 64 50 No correlation
Pain, belching, weight
Tack et al., 20019 160 34
loss
36
Boeckxstaens et al., 2002 44 48 No correlation
View Table in HTML
Perception of gastric distention requires the activation of mechanoreceptors, and studies in
healthy volunteers have suggested involvement of “in series” mechanoreceptors that respond to
increases in tension within the stomach wall.48, 49 By analyzing the relationship between changes
in perception and increases in pressure in an isovolumetric balloon in the proximal stomach, we
were able to show that dyspeptic patients with hypersensitivity to gastric distention perceive
isovolumetric phasic contractions of the proximal stomach.50 Fundus-relaxing drugs decrease
sensitivity to gastric distention and decrease meal-induced symptoms in these patients.50 These
findings are compatible with involvement of tension mechanoreceptors in the symptom
generation in dyspeptic patients with visceral hypersensitivity.

Because patients with hypersensitivity to gastric distention have more prevalent symptoms of
epigastric pain9, 17 and because they experience pain during gastric balloon distention at levels of
distention that are normally not painful, these patients have visceral hyperalgesia.43, 44, 45
According to the neurophysiologic theory of pain, pain can be encoded by activation of high-
threshold nociceptive pathways or by intense stimulation of low-threshold multimodal
pathways.51 To determine whether gastric hypersensitivity in functional dyspepsia reflects a
selective sensitization for painful sensations or whether the sensitivity for nonpainful stimuli is
also enhanced in patients with visceral hypersensitivity, we analyzed the relationship between
intensity scores for pain and nonpainful sensations during gastric balloon distention in
dyspepsia.52 In both normosensitive and hypersensitive dyspeptic patients, the elevation of
intensity scores for pain paralleled the elevation of intensity scores for the nonpainful sensations
of nausea, satiety, and fullness. These findings are compatible with up-regulation of multimodal
afferent pathways and argue against isolated up-regulation of pain-specific afferent pathways in
functional dyspepsia with visceral hyperalgesia.

Dyspeptic symptoms are usually triggered or aggravated by meal ingestion, suggesting that
sensitivity to gastric distention in the postprandial period might be involved in symptom
generation. In a preliminary study, we showed that postprandial sensitivity to gastric distention,
but not fasting sensitivity, was indeed related to the severity of meal-related symptoms in
functional dyspepsia.53

H. pylori infection

Soon after the discovery of H. pylori, a causal relationship between H. pylori infection and the
occurrence of duodenal and gastric ulcers was established.51In functional dyspepsia, the role of
H. pylori is less clear. A recent systematic review of the epidemiologic evidence on a
relationship between H. pylori infection and functional dyspepsia found no evidence for a strong
association. However, according to the investigators, many of the studies had important
weaknesses in design and execution and there was not enough evidence to rule out a modest
association.55

Several studies have investigated the association between H. pylori infection and dyspeptic
symptoms or pathophysiologic mechanisms.28, 56, 57, 58, 59, 60, 61 However, no consistent
differences in the prevalence and severity of individual dyspeptic symptoms, gastric emptying
rate, gastric relaxation after a meal, and sensitivity to gastric distention were found between H.
pylori-positive and H. pylori-negative subjects. Initial studies reported associations between H.
pylori infection and epigastric pain or burning,56 delayed gastric emptying,57 or impaired
accommodation.58 However, more recent and larger-scale studies failed to find any of these
correlations.59, 60, 61

Altered duodenal sensitivity to lipids or acid

Dyspeptic symptoms in functional dyspepsia are commonly exacerbated by meals rich in fat.62
Studies in health have shown that duodenal infusion of lipids, but not glucose, induces a
relaxation of the proximal stomach and enhances the sensitivity to proximal stomach
distention.63, 64 These influences of duodenal lipid infusion require lipid digestion and
subsequent release of cholecystokinin,64, 65 and they can be blocked by administration of a lipase
inhibitor or a cholecystokinin-A receptor antagonist.64, 65, 66 It was reported that increased
sensitivity to duodenal lipid infusion may be a relevant pathophysiologic mechanism in
functional dyspepsia.67, 68 However, the numbers of patients studied in this manner remained
small, and it is unclear whether this affects a subgroup of dyspeptic patients or all dyspeptic
patients (Table 5). Furthermore, all of these studies used intraduodenal mode administration, and
recent data have shown that observations derived from intraduodenally administered lipids do
not necessarily apply to orally ingested lipid-containing meals.69, 70

Table 5Literature Studies on Duodenal Hypersensitivity in Functional Dyspepsia

Study n Technique Conclusion
Duodenal lipid infusion, Duodenal lipids sensitize the stomach
Barbera et 10 patients10
duodenal saline infusion, to distention in patients with
al., 199568 controls
gastric balloon distention dyspepsia but not in controls
Duodenal lipid infusion, Duodenal lipids but not glucose
Barbera et 9 patients9
duodenal glucose infusion, sensitize the stomach to distention in
al., 199567 controls
gastric balloon distention dyspepsia
Duodenal acid infusion, Acid clearance is decreased in
Samsom et 12 patients
duodenal manometry and pH dyspepsia; hypersensitivity to
al., 199971 10 controls
monitoring duodenal acid induces nausea
Duodenal lipid infusion,
Feinle et al., CCK-A receptors are involved in
12 patients gastric balloon distention,
200166 sensitization by duodenal lipids
CCK-A antagonist
View Table in HTML

CCK, cholecystokinin.

Duodenal infusion of hydrochloric acid was found to induce nausea in a small group of patients
with functional dyspepsia but not in healthy controls, suggesting duodenal hypersensitivity to
acid. Furthermore, previous studies have shown that the duodenal motor response to acid was
decreased in patients with functional dyspepsia, resulting in reduced clearance of exogenous
duodenal acid.71 We confirmed that spontaneous duodenal acid exposure to endogenous acid was
increased in patients with functional dyspepsia who displayed delayed clearance of exogenous
duodenal acid.72 Patients with functional dyspepsia with duodenal acid exposure above the
normal range had higher severity scores of several dyspeptic symptoms. However, the severity of
individual symptoms was weakly correlated to duodenal pH and brief duodenal acid infusion did
not affect any symptoms, suggesting that duodenal acid exposure is poorly related to symptom
severity.72

Altered antroduodenojejunal motility

Manometry studies in functional dyspepsia have shown antral hypomotility to be a common

feature.73 It is presently unclear whether this reflects true hypomotility or a poor registration of
contractions in a dilated antrum in patients with impaired accommodation, because manometry
only registers lumen-obliterating contractions.8, 30, 31, 32, 73 Small bowel motor alterations, usually
hypermotility with burst activity or clusters, and an increased proportion of duodenal retrograde
contractions have been reported.74, 75 No clear correlation with symptoms has been found.74, 75

Abnormalities of gastric electrical rhythm

There is also evidence that abnormalities in the underlying gastric myoelectrical activity, as
measured by cutaneous electrogastrography, are found in up to two thirds of patients with
functional dyspepsia.76, 77 The relevance of this finding for gastric emptying and symptom
patterns remains to be established. No correlation was found between dyspeptic symptom pattern
and the presence of findings on electrogastrography. A good correlation between the presence of
delayed gastric emptying and abnormalities of gastric electrical rhythm has been reported.76, 77

Unsuppressed postprandial phasic contractility in the proximal stomach

Besides the relaxatory response of the proximal stomach after a meal, other motor aspects of the
proximal stomach have not been particularly frequently addressed in the literature. With the
barostat technique, it is also possible to detect phasic volume fluctuations from the baseline
volumes (“volume waves”), reflecting contractions superimposed on the background state of
contractility or tone.78 These contractions occur at a frequency that differs from antral
contraction waves.59, 78, 79 One study suggested the occurrence of increased phasic volume events
in the postprandial period in patients with functional dyspepsia.59 In a recent study, we observed
that, compared with healthy controls, a small subset (15%) of dyspeptic patients displayed
unsuppressed postprandial phasic contractility of the proximal stomach.79 Persistence of
postprandial phasic contractions of the proximal stomach was associated with H. pylori infection
and relevant or severe bloating, but also with the absence of nausea. The abnormality is of
potential relevance because phasic fundic contractions induce transient increases in gastric wall
tension, which can be perceived in functional dyspepsia.50

Autonomic nervous system/central nervous system dysregulation

Abnormalities within the autonomic nervous system have been suggested to be of importance in
some patients with functional dyspepsia. More specifically, an efferent vagal dysfunction has
been observed in several studies80, 81 and has been proposed to be a possible mechanism
underlying impaired accommodation to a meal82 and antral hypomotility.80 Furthermore, there is
evidence of an association between psychopathology and functional dyspepsia83 and between
psychological factors and gastric functioning and symptoms in functional dyspepsia, for which
low vagal activity was proposed to be the mediating mechanism.84, 85

In a recent factor analysis of dyspeptic symptoms and their relationship with physiopathology
and psychopathology, the heterogeneity and complexity of these interactions was clearly shown.
Factor analysis identified 4 separate symptom factors within functional dyspepsia, each of which
was associated with a measurable abnormality of gastric function, and of which 2 were
associated with specific psychosocial characteristics.17 The factor that consists of nausea,
vomiting, early satiety, and weight loss was associated with female sex and physician visits and
sickness leave, and the factor that consists of epigastric pain was associated with several
psychosocial dimensions, including medically unexplained symptoms and conditions, and with
low health-related quality of life.17

Relevance of putative pathophysiologic mechanisms to symptom generation

Although several pathophysiologic abnormalities are related to the dyspepsia symptom pattern
and severity, as summarized in the previous section, this does not establish causality. It is
conceivable that both simply coexist or that both depend on a presently unspecified causal
mechanism. A close correlation between presence and severity of a certain pathophysiologic
abnormality and presence and severity of certain symptoms adds strength to the association
between both. A very strong case is made when induction of a pathophysiologic abnormality in
healthy subjects also induces dyspeptic symptoms.

Delayed gastric emptying

The studies investigating the relationship between delayed emptying and symptom pattern
generally used questionnaires that assessed symptom severity over a time frame of weeks to
months, whereas the emptying test reflects the situation at a single point in time. Several studies
have shown that gastric emptying in functional dyspepsia has large intraindividual variability.19,
86
Attempts have been made to find a better correlation between symptoms and emptying rate by
assessing symptom severity during the measurement of the emptying rate of a standardized
meal.18, 19 However, this did not result in a better correlation between symptoms and emptying
rate.

Furthermore, induction of delayed gastric emptying in healthy subjects by pharmacologic or

dietary interventions is not associated with the occurrence of dyspeptic symptoms.87 These
observations question the relevance of delayed emptying as a mechanism underlying dyspeptic
symptoms.

Impaired accommodation

A close correlation exists between impairment of gastric accommodation, severity of early

satiety, and the amount of liquid meal ingested at maximum satiety during a slow satiety
drinking test.88 Erythromycin and motilin induce a contraction of the proximal stomach.89, 90
When these agonists are administered at the time of meal ingestion, this results in impaired
accommodation and is associated with early satiety.88, 98Relaxation of the proximal stomach can
be activated by duodenal distention or nutrient infusion via a vagovagal reflex pathway,92, 93 and
it requires activation of intrinsic nitrergic neurons in the stomach.94 Administration of a nitric
oxide synthase inhibitor induces impaired accommodation in humans, and this is associated with
early satiety.95 These observations add further support to the hypothesis that impaired
accommodation is the mechanism underlying the symptom of early satiety.

Hypersensitivity to gastric distention

One study found an association between hypersensitivity to gastric distention, as determined by a

gastric barostat study, and symptoms of pain and belching.9 However, this apparent association
could be influenced by a bias to report pain. In keeping with this possibility, a significant
association was found between symptoms of pain, hypersensitivity to gastric distention, and
several psychopathologic mechanisms, including neuroticism, somatization, a history of abuse,
and health-related quality of life dimensions. Attempts to induce hypersensitivity in healthy
subjects using a nitric oxide synthase inhibitor were not successful.95, 96 Recent data showed that
the N-methyl-d-aspartate receptor antagonist dextromethorphan sensitized the stomach to
distention in the absence of an effect on gastric compliance.97 However, this drug is not very
selective, and it is unclear whether this constitutes a valid model of visceral hypersensitivity and
whether pretreatment with an N-methyl-d-aspartate antagonist induces dyspepsia-like symptoms
after ingestion of a meal.

Other mechanisms

Acute H. pylori infection induces dyspepsia-like symptoms, but these are transient.98 Nausea
induced by vestibular stimulation is also associated with abnormalities of gastric electrical
rhythm, suggesting that this may be a secondary phenomenon accompanying nausea rather than a
primary mechanism.99 These observations question the direct pathophysiologic relevance of H.
pylori and gastric electrical dysrhythmias.

In healthy subjects, duodenal acid infusion sensitizes the proximal stomach and the duodenum to
distention and is able to induce dyspepsia-like symptoms.100, 101 Administration of the
cholinesterase inhibitor neostigmine before a meal induces unsuppressed postprandial phasic
contractions in healthy subjects, and this is associated with increased scores for several dyspeptic
symptoms.102 These observations suggest that increased duodenal acid exposure and
unsuppressed postprandial phasic contractility of the proximal stomach are mechanisms
potentially involved in the pathogenesis of dyspeptic symptoms. Table 6 summarizes the
reported associations between symptom patterns and pathophysiologic mechanisms in functional
dyspepsia.

Table 6Summary of Reported Associations Between Pathophysiologic Mechanisms and

Symptom Pattern in Functional Dyspepsia
Mechanism Associated symptoms References
7, 11, 17, 36
Delayed gastric emptying Postprandial fullness, nausea, vomiting
Hypersensitivity to gastric distention Epigastric pain, belching, weight loss 9, 17
8, 10, 35, 36
Impaired accommodation Early satiety, weight loss
 14, 28, 56
H. pylori infection Epigastric pain
66, 67, 68
Duodenal lipid hypersensitivity Nausea
71
Duodenal acid hypersensitivity Nausea
79
Unsuppressed phasic contractility Bloating, absence of nausea
111
Atypical nonerosive reflux disease Epigastric pain
View Table in HTML

Pathogenesis

The pathogenesis of functional dyspepsia is obscure, but a postinfectious or inflammatory origin

has been suggested for irritable bowel syndrome.103 Moreover, gastroparesis has been reported
after a viral infection.104 Using a questionnaire in 400 consecutive patients with functional
dyspepsia, we found that 17% had a history with acute onset, suggestive of a postinfectious
origin.10 These patients had a particularly high prevalence of impaired accommodation. Because
the proximal stomach in these patients relaxed to administration of a nitric oxide donor but did
not respond to sumatriptan, which releases nitric oxide through activation of 5-
hydroxytryptamine (5-HT)1 receptors on nitrergic neurones, the abnormality is attributable to a
dysfunction at the level of gastric nitrergic neurons.10

As previously mentioned, whether psychological factors have a pathogenetic role in functional

dyspepsia, especially in patients with hypersensitivity to gastric distention, or whether they are
disease modulators determining health care seeking, perception of symptoms, and the outcome of
the disorder is not known. There are several sources of evidence for a role of the central nervous
system in visceral hypersensitivity. Studies in experimental animals indicate that acute
psychological stress facilitates increased sensitivity to visceral stimuli.105 In line with such a
finding, rats genetically predisposed to anxiety have been shown to display an increased visceral
sensitivity.106 Similarly, in humans, the perception of gut distention has been found to be reduced
during periods of distraction and increased during periods of attentiveness or during mental
stress associated with anxiety.107 However, the role of central factors and stress in visceral
hypersensitivity and symptom generation in functional dyspepsia remains to be established.

Finally, an association between dyspeptic symptoms and a functional polymorphism in a G-

protein subunit was reported.108 It remains to be established whether this genotype is associated
with any specific pathophysiologic mechanism, the likelihood of postinfectious functional
disorders, or altered psychosocial features.

Clinical presentation and diagnosis

Patients with predominant heartburn or acid regurgitation should, according to the Rome II
criteria, not be included in the dyspeptic spectrum but should be referred to as having
gastroesophageal reflux disease because the management differs substantially.5 It has been
proposed that a substantial number of patients with predominant discomfort or pain centered in
the upper abdomen actually have atypical reflux disease.109 However, by using a simple
questionnaire to screen for reflux symptoms,110 only a minority of patients with predominant
dyspeptic symptoms have pathologic reflux as shown by 24-hour pH measurement.111 The use of
these questionnaires in clinical practice may prove useful to detect patients who actually have
reflux disease, with a higher likelihood of being responders to treatment with proton pump
inhibitors (PPIs).

There is also a huge overlap between functional dyspepsia and irritable bowel syndrome.2 For
instance, in a referral center, 46% of patients with functional dyspepsia proved to have
concomitant irritable bowel syndrome, and these patients were more likely to be female, have
gastric hypersensitivity, and have more severe symptoms in general.112 Furthermore, many
subjects change from predominant dyspeptic symptoms to bowel-related symptoms, indicating
irritable bowel syndrome, or the opposite during a 1-year follow-up period.2

When a patient presents with dyspeptic symptoms, careful clinical evaluation and history taking
are essential features to make a correct diagnosis of dyspepsia and to distinguish it from
gastroesophageal reflux disease and irritable bowel syndrome. Routine biochemistry is usually
included in the diagnostic workup, but the clinical value of this has not been formally validated.
So-called alarm symptoms (prominent weight loss, recurrent vomiting, bleeding, anemia,
dysphagia, jaundice, palpable mass) should be looked for with great care and, if present, require
additional diagnostic investigation. If there are no sinister symptoms and the patient is young
(younger than 45–50 years) and does not take nonsteroidal anti-inflammatory drugs, upper
endoscopy is rarely needed in the first line. However, early endoscopy is of course the gold
standard in the diagnostic workup of dyspeptic patients with more severe symptoms and may be
associated with greater patient satisfaction,113 but it is not possible to perform this procedure in
all patients because of financial, practical, and patient-related factors and other factors such as
availability. Instead, other strategies can be considered, namely initial empirical therapy114, 115,
116
or a “test and treat” approach.54

The American Gastroenterological Association presented a medical position statement regarding

the evaluation of dyspepsia in 1998 and recommended the “test and treat” strategy,117 meaning
initial testing for the presence of H. pylori infection and, if present, eradication therapy. H.
pylori-negative patients should be offered empirical antisecretory or prokinetic therapy. Based on
the existing studies on the effect of H. pylori eradication on functional dyspepsia,55 it can be
assumed that most patients will still be symptomatic after treatment of H. pylori and should in
that case be offered endoscopy. These guidelines were recently questioned by Spiegel et al., who
by using a so-called decision analysis found empirical PPI therapy to be more cost effective,
either as a first step or following a “test and treat” approach, when the patient has not responded
favorably to eradication therapy.118 Moreover, these decision analyses cannot be extrapolated to
every country because of major differences in the prevalence of H. pylori infection, prevalence
of ulcers, accessibility of endoscopy, and cost of endoscopy. A head-to-head comparison of these
strategies is needed, but in the meantime both strategies may be used and have support in the
literature. Although often used in clinical practice, the empirical prokinetic therapy has been less
well studied. An in-depth analysis of clinical management steps in dyspepsia was recently
published in Gastroenterology.119 In general practice, the initial empirical therapy is probably
still the most widely used approach. A clinical management algorithm based on currently
available management guidelines and clinical experience is summarized in Figure 3.
Figure 3

A clinical management algorithm based on currently available management guidelines and

clinical experience.

View Large Image | Download PowerPoint Slide

Other investigations that might be considered in the workup are, for instance, upper abdominal
ultrasonography or computed tomography, small bowel radiography, duodenal biopsy to exclude
celiac disease, 24-hour esophageal pH monitoring, and manometric studies of the upper
gastrointestinal tract. These investigations should not be performed in all patients but instead
should be based on the clinical picture, severity of symptoms, and refractoriness of the patient.

Psychological symptoms are also common in patients with functional dyspepsia as compared
with patients with organic causes of dyspepsia, such as duodenal ulcer.83 This may be more
related to being a patient seeking health care for dyspepsia than related to dyspepsia per se. A
review found several psychosocial factors such as life event stress, psychological morbidity,
personality, abuse history, and abnormal illness behavior and beliefs to be important factors in
the process that determines who will seek medical attention.120 The presence of psychosocial
factors in these patients should be addressed carefully but should not be overemphasized because
a causal role has not been established so far.

Treatment

General measures

Reassurance and education is of primary importance in patients with functional dyspepsia. It has
been shown in irritable bowel syndrome that a positive physician-patient interaction can reduce
health care seeking, and these findings are probably also valid for functional dyspepsia.121
Lifestyle and dietary measures are usually prescribed, although they have not been
systematically studied. It seems logical to have patients eat more frequent, smaller meals and
desirable to avoid food that aggravates symptoms. Because the presence of lipids in the
duodenum enhances the mechanosensitivity of the stomach, avoiding meals with a high fat
content might be advisable.67, 68 Coffee and spicy foods containing capsaicin are usually
discouraged, although there is no evidence to link these food components to symptoms.122, 123
In some patients, pharmacologic therapy will be considered. The pharmacologic treatments
available to date for the management of functional dyspepsia have only been shown to be of
limited efficacy. It seems logical that directing therapeutic approaches toward the underlying
pathophysiologic disturbances should increase the efficacy,124 but this has not been proven.

Acid-suppressive drugs

In patients with gastroesophageal reflux, a trial of antisecretory therapy has both therapeutic and
diagnostic value. Several studies have evaluated the use of H2-receptor antagonists in functional
dyspepsia, and a recent meta-analysis showed superiority over placebo in improvement of pain
but not for overall symptom improvement.125 PPIs have proven to be more effective than H2-
receptor antagonists and antacid-alginate in relieving symptoms of uninvestigated dyspepsia
(comparable to the initial empirical PPI treatment previously mentioned).114, 115, 116 Of course,
these studies not only included patients with functional dyspepsia but also patients with peptic
ulcer disease and with gastroesophageal reflux disease. Large and well-controlled studies in
functional dyspepsia have shown that treatment with omeprazole was approximately 10%–15%
better than placebo in patients with functional dyspepsia.15 However, this positive effect was
restricted to patients with reflux-like dyspepsia, a subgroup that actually is no longer considered
to belong to functional dyspepsia, and to a lesser degree in patients with ulcer-like dyspepsia. In
patients with dysmotility-like dyspepsia, no effect could be observed.15

In a recent study in consecutive patients with functional dyspepsia without dominant symptoms
of heartburn, pathologic esophageal acid exposure was present in a subset of patients who were
characterized by a higher prevalence of epigastric pain.111 This finding suggests that patients
with ulcer-like dyspepsia who respond to acid-suppressive therapy may actually have
gastroesophageal reflux disease. On the other hand, recent studies have suggested a role for
increased duodenal acid exposure and duodenal acid hypersensitivity in the pathogenesis of
functional dyspepsia.71, 72 Treatment with PPIs tended to decrease duodenal acid
hypersensitivity, but so far no symptomatic benefit in this group of patients has been shown.126

Prokinetic agents

Prokinetic agents, including metoclopramide, domperidone, and cisapride, are widely used in
functional dyspepsia. The rationale is to use prokinetic drugs in patients with delayed gastric
emptying, in which they should improve symptoms of postprandial fullness, nausea, and
vomiting. However, studies available so far fail to prove this hypothesis, and evidence that the
symptomatic improvement is related to enhancement of gastric emptying is lacking.127, 128, 129, 130

Metoclopramide and domperidone are dopamine receptor agonists with a stimulatory effect on
upper gastrointestinal motility. Unlike metoclopramide, domperidone does not cross the blood-
brain barrier. Cisapride facilitates the release of acetylcholine in the myenteric plexus via 5-HT4
receptor agonism and accelerates gastric emptying.127, 128, 129, 130 The availability of cisapride is
restricted due to cardiac safety issues. Recently, tegaserod, a partial 5-HT4 agonist, was found to
accelerate gastric emptying, indicating its possibility as a prokinetic agent.131
Recent reviews suggest that prokinetics, especially domperidone and cisapride, are more
effective than placebo, but the trials were often of poor quality with significant heterogeneity
between studies.127, 128, 129, 130 However, the gastroprokinetic effects of these drugs are limited,
and the finding of the strong gastrokinetic actions of erythromycin, a macrolide antibiotic that
acts as a motilin receptor agonist, was met with great enthusiasm.132 Several short-term studies
reported beneficial effects of treatment with erythromycin in gastroparesis.132, 133, 134 Different
macrolide prokinetics, devoid of antibiotic properties, were developed and one of these, ABT-
229, was studied in large clinical trials.135 However, the outcomes of clinical trials with ABT-
229 were unequivocally disappointing with regard to symptom improvement, both in dyspeptic
patients with and without delayed emptying. It has been argued that the negative outcomes of the
studies with ABT-229 show that acceleration of gastric emptying is not the correct therapeutic
target in functional dyspepsia,135 but there are also strong indications of tachyphylaxis with
macrolide prokinetics.136, 137 Furthermore, it is well established that erythromycin and related
compounds impair gastric accommodation to a meal,89, 90, 91 thereby enhancing sensitivity to
gastric distention,48 which may have contributed to the overall poor symptomatic effect.
Cisapride and tegaserod were shown to enhance gastric accommodation to a meal138, 139 and are
therefore less likely to worsen or induce symptoms related to impaired accommodation. In
addition, in preliminary studies, we showed a tendency for tegaserod to improve upper
gastrointestinal symptoms in female patients with functional dyspepsia with normal gastric
emptying, suggesting that it may affect pathophysiologic mechanisms other than delayed gastric
emptying.140

Eradication of H. pylori

The 4 largest published randomized trials on the effect of H. pylori eradication on symptoms in
functional dyspepsia show somewhat conflicting results. A single-center trial suggested a small
superiority of eradication treatment versus PPI treatment alone,141 but 3 multicenter trials had
negative findings.142, 143, 144 Taken together, these 4 large studies suggest that the potential
symptomatic benefit of H. pylori treatment in functional dyspepsia is probably of limited
importance. Other arguments in favor of the use of eradication therapy are protection against
peptic ulcer, putative protection against gastric cancer, and the short-term nature of the
treatment.145

Antidepressants

There is some evidence that tricyclic antidepressants are effective in treating patients with
functional gastrointestinal disorders, including functional dyspepsia.146, 147 Generally, lower
doses are used than for treatment of depression. Mianserin, at a high dose, was also shown to be
superior to placebo in patients with functional gastrointestinal disorders, including dyspepsia.148
The mechanism behind the positive effect has been proposed to be due to an effect on gastric
sensitivity, but this could not be confirmed in the study by Mertz et al.147 In clinical practice, it
seems that the positive effect is not clearly related to the presence or absence of depression. It is
unclear whether selective serotonin reuptake inhibitors (SSRIs) are also effective treatment
alternatives for functional gastrointestinal disorders. These drugs increase the availability of
synaptically released 5-HT not only in the central nervous system but also at the level of the
enteric nervous system. Pretreatment with the SSRI paroxetine strongly enhanced the meal-
induced relaxation of the proximal stomach in healthy subjects.149 This observation suggests
involvement of 5-HT in the gastric accommodation reflex in humans as well as a potential
beneficial effect of SSRIs in dyspeptic patients with impaired accommodation. In an open-label
study in dyspeptic patients with abnormalities on electrogastrography, only patients with
coexisting depression improved and gastric myoelectrical activity did not improve.150

Fundus-relaxing drugs

It seems logical that restoring gastric accommodation in patients with impaired accommodation
is likely to improve symptoms of early satiety. Short-term studies have shown some benefit of
nitrates,151 but prolonged use is generally associated with undesirable vascular side effects due to
the lack of specificity. Sildenafil blocks phosphodiesterase type 5, which degrades nitric oxide-
stimulated guanosine 3′,5′-cyclic monophosphate, thereby relaxing smooth muscle in various
organs. Pretreatment with sildenafil also relaxes the proximal stomach,152 and trials evaluating
phosphodiesterase inhibitors in functional dyspepsia seem warranted. Similar to the central
nervous system, serotonin reuptake in the enteric nervous system is also inhibited by SSRIs.153
The enhancement of gastric accommodation by pretreatment with the SSRI paroxetine suggests
involvement of 5-HT in the control of the accommodation reflex in humans.149 The 5-HT
receptor involved has not been identified, but both 5-HT1 and 5-HT4 receptors can mediate
enhanced postprandial gastric relaxation. Pretreatment with the 5-HT4 receptor agonists cisapride
and tegaserod enhances gastric accommodation in healthy subjects.138, 139 Administration of
sumatriptan, a 5-HT1 receptor agonist used in the treatment of migraine, relaxes the proximal
stomach in healthy subjects.154 In short-term studies, subcutaneous administration of sumatriptan
was shown to restore meal-induced relaxation in patients with impaired gastric accommodation
and to increase the amount of calories ingested at maximum satiety in patients with early satiety.8
Due to its pharmacologic properties, cost, and mode of administration, subcutaneous sumatriptan
is not suitable for long-term treatment of functional dyspepsia. A nasal-spray formulation of
sumatriptan had no significant effect on proximal stomach function.155 Buspirone is a
nonselective 5-HT1 receptor agonist used in the treatment of panic attacks. In a placebo-
controlled study in patients with functional dyspepsia, we confirmed that buspirone was superior
to placebo in alleviating dyspeptic symptoms and that this was associated with an enhancement
of the accommodation to a meal.156 Clonidine, an α2 receptor agonist, also relaxes the stomach
and reduces gastric sensation.157 Short-term administration of clonidine was found to decrease
meal-induced symptoms in functional dyspepsia.50

Other drugs

Dose-finding studies with the 5-HT3 receptor antagonist alosetron showed potential benefit in
functional dyspepsia.158 The mechanisms behind its effect are at present unclear. No effect on
gastric sensitivity in healthy volunteers has been shown,159 but 5-HT3 receptor antagonism
reduces duodenal lipid sensitivity.63 Alosetron was on the U.S. market for approximately 6
months for diarrhea-predominant irritable bowel syndrome, but its use is now restricted due to
safety issues.160

Cholecystokinin receptor antagonists also reduce duodenal lipid sensitivity and are currently
under evaluation.64, 66 The κ opioid agonist fedotozine decreases gastric sensitivity to
distentions,161 and it showed superiority over placebo in a placebo-controlled study in patients
with functional dyspepsia.162 However, development of this drug has not continued.
Asimadoline, another κ opioid agonist that was shown to decrease satiation and meal-induced
fullness,163 is currently still under evaluation.

A recent study showed that long-term administration of red pepper was more effective than
placebo in decreasing the intensity of dyspeptic symptoms in patients with functional
dyspepsia.123 Such a contradictory result might be explained by the finding that capsaicin
initially produces sensitization but repeated stimulation of the capsaicin receptor on capsaicin-
sensitive primary afferents leads to desensitization.164 Studies of the effect of capsaicin on gastric
sensitivity in humans, which showed acute sensitization followed by decreased perception of
epigastric symptoms,165 are in keeping with this mechanism of action. In a controlled trial in
patients with functional dyspepsia, artichoke leaf extract was significantly better than placebo in
alleviating symptoms and in improving quality of life.166 The basis for this improvement remains
to be identified.

Psychological interventions

Psychological factors are considered important contributors to symptom severity in patients with
functional gastrointestinal disorders, including functional dyspepsia.8, 167 This suggests that
psychological treatment alternatives might be useful in these patients.

A review of clinical trials of psychological interventions for functional dyspepsia showed

potential benefits in the treatment of functiona

l dyspepsia.168 However, several studies did not control for additional time and attention the
patients received in the psychological intervention arms, making it difficult to exclude a
contribution of nonspecific factors. Another study controlled for this factor compared
psychodynamic-interpersonal psychotherapy with supportive therapy in 95 consecutive patients
with functional dyspepsia who had failed to respond to conventional pharmacologic
treatments.169 At the end of treatment, patients receiving psychotherapy had a significantly better
outcome than those receiving supportive therapy. One year after treatment, the symptom scores
were similar in both groups, but a post hoc analysis excluding patients with severe heartburn also
showed a positive effect of psychotherapy at 1 year. Hypnotherapy was also shown to be useful
in functional dyspepsia in a randomized study compared with supportive or medical therapy.170
In a follow-up of 1 year, the effect was maintained. Hence, assessing psychosocial issues and
intervening at this level in patients with functional dyspepsia seems to be a reasonable approach.
However, in clinical practice, this approach is usually reserved for those with severe and
extensive symptomatology or refractory disease.

Conclusions

Functional dyspepsia is one of the most common disorders seen in general practice and by
gastroenterologists. Functional dyspepsia seems to be a heterogenous disorder in which different
pathophysiologic disturbances are associated with different symptom profiles. The available
options for the treatment of functional dyspepsia are of limited efficacy, which probably reflects
the incomplete understanding of the nature of this disorder. Current knowledge is in support of
empirical treatment with acid-suppressive agents and prokinetics as well as identification and
treatment of H. pylori infection. Refractory patients may benefit from treatment with
antidepressants or psychological interventions. More effective approaches are badly needed, and
this will probably require ongoing efforts to elucidate underlying pathophysiology.

Gastritis

GASTRITIS
The term gastritis should be reserved for histologically documented
inflammation of the gastric mucosa. Gastritis is not the mucosal
erythema seen during endoscopy and is not interchangeable with
“dyspepsia.” The etiologic factors leading to gastritis are broad and
heterogeneous. Gastritis has been classified based on time course
(acute vs chronic), histologic features, and anatomic distribution or
proposed pathogenic mechanism (Table 348-9).
The correlation between the histologic findings of gastritis, the clinical
picture of abdominal pain or dyspepsia, and endoscopic findings
noted on gross inspection of the gastric mucosa is poor. Therefore,
there is no typical clinical manifestation of gastritis.
Acute Gastritis The most common causes of acute gastritis are infectious.
Acute infection with H. pylori induces gastritis. However, H.
pylori acute gastritis has not been extensively studied. It is reported as
presenting with sudden onset of epigastric pain, nausea, and vomiting,
and limited mucosal histologic studies demonstrate a marked infiltrate
of neutrophils with edema and hyperemia. If not treated, this picture
will evolve into one of chronic gastritis. Hypochlorhydria lasting for up
to 1 year may follow acute H. pylori infection.
Bacterial infection of the stomach or phlegmonous gastritis is a rare,
potentially life-threatening disorder characterized by marked and diffuse
acute inflammatory infiltrates of the entire gastric wall, at times
accompanied by necrosis. Elderly individuals, alcoholics, and AIDS
patients may be affected. Potential iatrogenic causes include polypectomy
and mucosal injection with India ink. Organisms associated with
this entity include streptococci, staphylococci, Escherichia coli, Proteus,
and Haemophilus species. Failure of supportive measures and antibiotics
may result in gastrectomy.
TABLE 348-9 CLASSIFICATION OF GASTRITIS
I. Acute gastritis
A. Acute H. pylori infection
B. Other acute Infectious gastritides
1. Bacterial (other than H. pylori)
2. H. heilmannii
3. Phlegmonous
4. Mycobacterial
5. Syphilitic
6. Viral
7. Parasitic
8. Fungal
II. Chronic atrophic gastritis
A. Type A: Autoimmune, body-predominant
B. Type B: H. pylori–related, antral-predominant
C. Indeterminate
III. Uncommon forms of gastritis
A. Lymphocytic
B. Eosinophilic
C. Crohn’s disease
D. Sarcoidosis
E. Isolated granulomatous gastritis
F. Russell body gastritis
Other types of infectious gastritis may occur in immunocompromised
individuals such as AIDS patients. Examples include herpetic
(herpes simplex) or CMV gastritis. The histologic finding of intranuclear
inclusions would be observed in the latter.
Chronic Gastritis Chronic gastritis is identified histologically by an
inflammatory cell infiltrate consisting primarily of lymphocytes and
plasma cells, with very scant neutrophil involvement. Distribution of
the inflammation may be patchy, initially involving superficial and
glandular portions of the gastric mucosa. This picture may progress
to more severe glandular destruction, with atrophy and metaplasia.
Chronic gastritis has been classified according to histologic characteristics.
These include superficial atrophic changes and gastric atrophy.
The association of atrophic gastritis with the development of gastric
cancer has led to the development of endoscopic and serologic markers
of severity. Some of these include gross inspection and classification
of mucosal abnormalities during standard endoscopy, magnification
endoscopy, endoscopy with narrow band imaging and/or autofluorescence
imaging, and measurement of several serum biomarkers including
pepsinogen I and II levels, gastrin-17, and anti-H. pylori serologies.
The clinical utility of these tools is currently being explored.
The early phase of chronic gastritis is superficial gastritis. The
inflammatory changes are limited to the lamina propria of the surface
mucosa, with edema and cellular infiltrates separating intact gastric
glands. The next stage is atrophic gastritis. The inflammatory infiltrate
extends deeper into the mucosa, with progressive distortion and
destruction of the glands. The final stage of chronic gastritis is gastric
atrophy. Glandular structures are lost, and there is a paucity of inflammatory
infiltrates. Endoscopically, the mucosa may be substantially
thin, permitting clear visualization of the underlying blood vessels.
Gastric glands may undergo morphologic transformation in
chronic gastritis. Intestinal metaplasia denotes the conversion of
gastric glands to a small intestinal phenotype with small-bowel mucosal
glands containing goblet cells. The metaplastic changes may vary
in distribution from patchy to fairly extensive gastric involvement.
Intestinal metaplasia is an important predisposing factor for gastric
cancer (Chap. 109).
Chronic gastritis is also classified according to the predominant site
of involvement. Type A refers to the body-predominant form (autoimmune),
and type B is the antral-predominant form (H. pylori–related).
CHAPTER 348 Peptic Ulcer Disease and Related Disorders
1931
FIGURE 348 14 Chronic gastritis and H. pylori organisms. Steiner
silver stain of superficial gastric mucosa showing abundant darkly
stained microorganisms layered over the apical portion of the surface
epithelium. Note that there is no tissue invasion.
This classification is artificial in view of the difficulty in distinguishing
between these two entities. The term AB gastritis has been used to refer
to a mixed antral/body picture.
TYPE A GASTRITIS The less common of the two forms involves primarily
the fundus and body, with antral sparing. Traditionally, this form of
gastritis has been associated with pernicious anemia (Chap. 128) in
the presence of circulating antibodies against parietal cells and IF; thus,
it is also called autoimmune gastritis. H. pylori infection can lead to a
similar distribution of gastritis. The characteristics of an autoimmune
picture are not always present.
Antibodies to parietal cells have been detected in >90% of patients
with pernicious anemia and in up to 50% of patients with type A
gastritis. The parietal cell antibody is directed against H+,K+-ATPase.
T cells are also implicated in the injury pattern of this form of gastritis.
A subset of patients infected with H. pylori develop antibodies against
H+,K+-ATPase, potentially leading to the atrophic gastritis pattern seen
in some patients infected with this organism. The mechanism is thought
to involve molecular mimicry between H. pylori LPS and H+,K+-ATPase.
Parietal cell antibodies and atrophic gastritis are observed in family
members of patients with pernicious anemia. These antibodies
are observed in up to 20% of individuals over age 60 and in ~20% of
patients with vitiligo and Addison’s disease. About one-half of patients
with pernicious anemia have antibodies to thyroid antigens, and about
30% of patients with thyroid disease have circulating antiparietal cell
antibodies. Anti-IF antibodies are more specific than parietal cell
antibodies for type A gastritis, being present in ~40% of patients with
pernicious anemia. Another parameter consistent with this form of
gastritis being autoimmune in origin is the higher incidence of specific
familial histocompatibility haplotypes such as HLA-B8 and HLA-DR3.
The parietal cell–containing gastric gland is preferentially targeted
in this form of gastritis, and achlorhydria results. Parietal cells are the
source of IF, the lack of which will lead to vitamin B12 deficiency and its
sequelae (megaloblastic anemia, neurologic dysfunction).
Gastric acid plays an important role in feedback inhibition of
gastrin release from G cells. Achlorhydria, coupled with relative sparing
of the antral mucosa (site of G cells), leads to hypergastrinemia.
Gastrin levels can be markedly elevated (>500 pg/mL) in patients
with pernicious anemia. ECL cell hyperplasia with frank development
of gastric carcinoid tumors may result from gastrin trophic effects.
Hypergastrinemia and achlorhydria may also be seen in nonpernicious
anemia–associated type A gastritis.
TYPE B GASTRITIS Type B, or antral-predominant, gastritis is the more
common form of chronic gastritis. H. pylori infection is the cause of
this entity. Although described as “antral-predominant,” this is likely
a misnomer in view of studies documenting the progression of the
inflammatory process toward the body and fundus of infected individuals.
The conversion to a pangastritis is time-dependent and estimated
to require 15–20 years. This form of gastritis increases with age, being
present in up to 100% of persons over age 70. Histology improves after
H. pylori eradication. The number of H. pylori organisms decreases
dramatically with progression to gastric atrophy, and the degree of
inflammation correlates with the level of these organisms. Early on,
with antral-predominant findings, the quantity of H. pylori is highest
and a dense chronic inflammatory infiltrate of the lamina propria is
noted, accompanied by epithelial cell infiltration with polymorphonuclear
leukocytes (Fig. 348-14).
Multifocal atrophic gastritis, gastric atrophy with subsequent metaplasia,
has been observed in chronic H. pylori–induced gastritis.
This may ultimately lead to development of gastric adenocarcinoma
(Fig. 348-8; Chap. 109). H. pylori infection is now considered an
independent risk factor for gastric cancer. Worldwide epidemiologic
studies have documented a higher incidence of H. pylori infection
in patients with adenocarcinoma of the stomach as compared to
control subjects. Seropositivity for H. pylori is associated with a threeto
sixfold increased risk of gastric cancer. This risk may be as high as
ninefold after adjusting for the inaccuracy of serologic testing in the
elderly. The mechanism by which H. pylori infection leads to cancer
is unknown, but it appears to be related to the chronic inflammation
induced by the organism. Eradication of H. pylori as a general preventative
measure for gastric cancer is being evaluated but is not yet
recommended.
Infection with H. pylori is also associated with development of a
low-grade B cell lymphoma, gastric MALT lymphoma (Chap. 134).
The chronic T cell stimulation caused by the infection leads to production
of cytokines that promote the B cell tumor. The tumor should
be initially staged with a CT scan of the abdomen and EUS. Tumor
growth remains dependent on the presence of H. pylori, and its eradication
is often associated with complete regression of the tumor. The
tumor may take more than a year to regress after treating the infection.
Such patients should be followed by EUS every 2–3 months. If the
tumor is stable or decreasing in size, no other therapy is necessary. If
the tumor grows, it may have become a high-grade B cell lymphoma.
When the tumor becomes a high-grade aggressive lymphoma histologically,
it loses responsiveness to H. pylori eradication.
TREATMENT CHRONIC GASTRITIS
Treatment in chronic gastritis is aimed at the sequelae and not
the underlying inflammation. Patients with pernicious anemia will
require parenteral vitamin B12 supplementation on a long-term
basis. Eradication of H. pylori is often recommended even if PUD or a
low-grade MALT lymphoma is not present.
Miscellaneous Forms of Gastritis Lymphocytic gastritis is characterized
histologically by intense infiltration of the surface epithelium with
lymphocytes. The infiltrative process is primarily in the body of the
stomach and consists of mature T cells and plasmacytes. The etiology
of this form of chronic gastritis is unknown. It has been described
in patients with celiac sprue, but whether there is a common factor
associating these two entities is unknown. No specific symptoms suggest
lymphocytic gastritis. A subgroup of patients have thickened folds
noted on endoscopy. These folds are often capped by small nodules
that contain a central depression or erosion; this form of the disease
is called varioliform gastritis. H. pylori probably plays no significant
role in lymphocytic gastritis. Therapy with glucocorticoids or sodium
cromoglycate has obtained unclear results.
Marked eosinophilic infiltration involving any layer of the stomach
(mucosa, muscularis propria, and serosa) is characteristic of eosinophilic
gastritis. Affected individuals will often have circulating eosinophilia
with clinical manifestation of systemic allergy. Involvement may
PART 14 Disorders of the Gastrointestinal System
1932 range from isolated gastric disease to diffuse eosinophilic gastroenteritis.
Antral involvement predominates, with prominent edematous folds
being observed on endoscopy. These prominent antral folds can lead to
outlet obstruction. Patients can present with epigastric discomfort, nausea,
and vomiting. Treatment with glucocorticoids has been successful.
Several systemic disorders may be associated with granulomatous
gastritis. Gastric involvement has been observed in Crohn’s disease.
Involvement may range from granulomatous infiltrates noted only on
gastric biopsies to frank ulceration and stricture formation. Gastric
Crohn’s disease usually occurs in the presence of small-intestinal disease.
Several rare infectious processes can lead to granulomatous gastritis,
including histoplasmosis, candidiasis, syphilis, and tuberculosis.
Other unusual causes of this form of gastritis include sarcoidosis, idiopathic
granulomatous gastritis, and eosinophilic granulomas involving
the stomach. Establishing the specific etiologic agent in this form
of gastritis can be difficult, at times requiring repeat endoscopy with
biopsy and cytology. Occasionally, a surgically obtained full-thickness
biopsy of the stomach may be required to exclude malignancy.
Russell body gastritis (RBG) is a mucosal lesion of unknown etiology
that has a pseudotumoral endoscopic appearance. Histologically, it
is defined by the presence of numerous plasma cells containing Russell
bodies (RBs) that express kappa and lambda light chains. Only 10 cases
have been reported, and 7 of these have been associated with H. pylori
infection. The lesion can be confused with a neoplastic process, but it
is benign in nature, and the natural history of the lesion is not known.
There have been cases of resolution of the lesion when H. pylori was
eradicated.
Pathway dispepsia
3. dyspepsia
https://www.scribd.com/document/117241878/Dyspepsia-pdf
4. patofisiologi acid gaster
https://www.youtube.com/watch?v=Rcb6I7gsl-Y
guyton hal 772
5. anatomy gaster
7. GERD
https://www.scribd.com/doc/44359177/Gastroesophageal-Refluks-GERD
8.
Perbedaan Antara Asam Lambung dan Maag Yang Harus Anda Ketahui!
By Hani Handayani | 3 Comments Obat Asam Lambung Meningkat Dan Maag,- Orang biasanya
cenderung mengkaitkan setiap keluhan di lambung dengan gastritis atau sakit maag. Padahal
tidak selalu setiap gangguan atau keluhan di lambung disebut Gastritis. Maka dari itu, Perbedaan
Antara Asam Lambung dan Maag Yang Harus Anda Ketahui agar nantinya dapat menangani
dengan tepat dan tidak salah kaprah. Maag merupakan gejala penyakit yang menyerang lambung
dikarenakan terjadi luka atau peradangan pada lambung yang menyebabkan sakit. Penyebabnya
bisa karena penderita memiliki pola makan yang buruk atau sebab lain. Bagi penderita maag
yang sudah parah, penyakit maag tersebut sangat berbahaya dan dapat menyebabkan kematian.
Maag bisa disembuhkan tetapi tidak bisa sembuh
total, maag adalah penyakit yang ‘kambuh’ apabila si
penderita tidak makan teratur, terlalu banyak makan, atau terlalu banyak makan makanan yang
terlalu asam, atau terlalu pedas. Sedangkan Asam Lambung atau GERD, adalah kondisi adanya
aliran balik dari isi lambung ke kerongkongan yang menyebabkan gejala yang mengganggu
hingga terjadi komplikasi. Aliran balik asam lambung ke kerongkongan tidak hanya menjadi
pemicu sindrom GERD (seperti naiknya aliran isi lambung ke kerongkongan atau regurgitasi
ataupun nyeri dada seperti terbakar, heartburn) tetapi juga menyebabkan luka pada
kerongkongan atau esofagitis. Alur balik isi lambung ini juga dilaporkan bisa menyebabkan
atypical syndrome (seperti asthma reflux) yang dapat mengganggu aktivitas sehari-hari dan sulit
untuk diobati. GERD / asam lambung ini disebabkan oleh
GERD yang tidak memiliki penanganan yang baik dapat menyebabkan terjadinya komplikasi
antara lain seperti penyempitan kerongkongan, pendarahan kerongkongan serta kondisi yang
disebut Barrett’s esophagu
s (terjadi pembentukan jaringan pada dinding kerongkongan seperti yang ditemukan dalam usus).
Jika hal ini terjadi, perjalanan penyakit ini berhubungan dengan kanker kerongkongan. Faktor
resiko seseorang untuk mengalami asam lambung adalah obesitasi, tidur terlentang setelah
makan, merokok, alkohol, kopi dan stres. Kopi dengan sendirinya akan meningkatkan asam
lambung, sama halnya dengan stress. Jika sesuatu yang salah terjadi di otak, maka otak akan
memerintahkan lambung untuk mempoduksi asam lambung berlebih.
9. peptic ulcer
https://www.scribd.com/doc/74027441/Referat-Ulkus-Peptikum
10. gastric cancer
https://www.roche.com/dam/jcr:c45550f7-55cd-4fa1-8eb8-6abb3db9f2d4/en/med-stomach-
cancer.pdf
https://www.medscape.com/viewarticle/579410
11. lab

 c

13.

14. Back pain is often caused by muscle strain or arthritis in your spine, but it can also be a sign
of a wide range of other causes. These causes may include pressure on the nerves in your spine, a
kidney infection, cancer, or other serious health conditions. Back pain can even be a sign of a
heart attack. Back pain can also spring up at the most unexpected times, while sitting or taking a
step, or even after eating.

If you have back pain after eating, you may assume that the discomfort is related to a digestive
problem. This could be the case, but it’s important to look at all your symptoms and any possible
triggers for pain.

Causes
Causes
The back is often the site of referred pain. Referred pain is pain that you experience in a part of
the body that is not the actual source of the discomfort. For example, a heart attack, which is a
problem with blood flow to the heart muscle, can cause pain to radiate from the heart into the
back and elsewhere.

Keep reading to learn more about possible causes for back pain after eating.

Ulcer and heartburn

Signs of digestive distress often include pains in your abdomen or reactions that include
vomiting or diarrhea. Depending on the condition, however, you could feel pain in your back as
well.

A peptic ulcer can cause referred pain in your back. This type of ulcer is a sore in your stomach
or the small intestines. Typical symptoms include:

 heartburn
 abdominal pain
 bloating
 gas

Ulcers can be mild or quite painful. For the more serious cases, pain can be felt in the back as
well.

Heartburn is another digestive disorder that may cause pain in your back. Symptoms of heartburn
caused by gastrointestinal reflux disease (GERD), include a burning sensation in the chest, a sour
taste in the mouth, and pain the middle of your back.

Posture

One of the most common causes of back pain is poor posture. If you sit hunched over your food
during a meal, you may finish eating with soreness in your back. That same pain can develop if
you’re hunched over your computer or if you maintain a slouched position most of the time.

Kidney infection

Your kidneys are situated near the muscles in the mid- to lower part of your back. When you
have a kidney infection, one of the symptoms you may notice is back pain near one or both of
your kidneys. Other symptoms, such as more frequent urination, a burning sensation when
urinating, and abdominal pain are also often present. A kidney infection is a potentially serious
health problem and should be treated promptly.

Heart attack

Back pain can be a sign of a heart attack. Other warning signs of a cardiac event include:

 chest pain
 pain in your neck, jaw, or arm
 nausea
 feeling lightheaded
 breaking into a sweat

Women are more likely than men to have non-traditional heart attack symptoms, such as back
and neck pain.
See a doctor
When to see a doctor
If back pain is your only symptom and you suspect it’s caused by muscle strain, you can try rest
and anti-inflammatory medications such as ibuprofen (Advil, Motrin), as long as your doctor has
told you it’s ok to take this type of medication, and see if you feel better in a few days. If the pain
persists for a week or more, or gets increasingly worse, then see a doctor.

If you have other symptoms along with back pain, you should consider seeing a doctor. This is
particularly true if you notice changes in urine, indicating a kidney problem, or tarry stools,
which could mean an ulcer or other serious condition.

A urinary tract infection (UTI) or bladder infection can progress to a kidney infection, so it’s
always best to get a diagnosis and treatment if these conditions are present. Likewise, an ulcer
can raise your risk of internal bleeding, so responding soon to symptoms is always a good idea.

When back pain is accompanied by pain running down one or both legs, it’s usually caused by a
nerve in your spine that’s being irritated. You should see your doctor if you have these
symptoms. They can recommend a variety of non-invasive or invasive treatments.

Treatment
Treatment
The usual treatment for a sore back includes rest, ice, and anti-inflammatory painkillers. A
musculoskeletal problem, such as a ruptured disc, arthritis, or inflamed muscles and tendons may
also be treated with physical therapy. In physical therapy, you’ll learn various stretching and
strengthening exercises to help support and stabilize your spine. Physical therapy, as well as
yoga and tai chi, can also help improve your posture.

When the pain is the result of other underlying health problems, treatments will vary
considerably. Antibiotics are necessary to treat a kidney infection. Antibiotics may also be used
to treat ulcers if there’s a bacterial infection present. Other ulcer and GERD medications include
drugs that are used to block or reduce stomach acid production.

What’s Causing My Epigastric Pain and How Can I Find Relief?

 Acid reflux
 Heartburn and indigestion
 Lactose intolerance
 Alcohol
 Overeating
 Hiatal hernia
  Esophagitis
 Gastritis
 Peptic ulcer disease
 Barrett’s esophagus
 Gallbladder inflammation or gallstones
 In pregnancy
 Treatment
 See your doctor

Is this cause for concern?

Epigastric pain is a name for pain or discomfort right below your ribs in the area of your upper
abdomen. It often happens alongside other common symptoms of your digestive system. These
symptoms can include heartburn, bloating, and gas.

Epigastric pain isn’t always cause for concern. This condition has many possible causes,
especially when it happens right after eating.

It’s important to be able to tell the difference between pain that’s a result of something harmless,
like overeating or lactose intolerance, and pain that happens because of an underlying condition,
such as GERD, inflammation, or infection.

Keep reading to learn more about what may be causing your symptoms.

Acid reflux
1. Acid reflux
Acid reflux happens when some of your stomach acid or the food in your stomach washes back
up into your esophagus. When this happens, it can cause pain in your chest and throat. Over
time, constant acid reflux can cause gastroesophageal reflux disease (GERD). GERD requires
regular monitoring by your doctor.

Common symptoms of acid reflux include:

 heartburn
 indigestion
 abnormal acidic taste in your mouth
 throat soreness or hoarseness
 feeling a lump in your throat
 ongoing cough

Learn more: What are the differences between heartburn, acid reflux, and GERD? »

Identifying gallbladder problems »

Heartburn and indigestion
2. Heartburn and indigestion
Heartburn is a result of acid reflux. This can cause burning chest pain. Indigestion (dyspepsia) is
a name for digestive symptoms that happen when you eat types of foods that don’t seem to agree
with you.

The most common symptom of heartburn is a burning feeling in your chest after you eat. This
burning feeling usually is worse when you lie or bend down. This is because the acid moves
farther up your esophagus.

Common symptoms of indigestion include:

 feeling bloated
 burping
 getting full even if you haven’t eaten much
 nausea
 pressure in your abdomen from gas

Learn more: How to stop overeating »

Lactose intolerance
3. Lactose intolerance
Lactose intolerance happens when your body has trouble digesting dairy products, such as milk
or cheese. Dairy products all contain a type of sugar called lactose. Typically, symptoms will
occur every time you eat dairy.

Lactose intolerance often develops when you don’t have enough lactase in your body. This
enzyme is important in breaking down the sugar lactose.

Common symptoms of lactose intolerance include:

 feeling bloated
 stomach pains
 pressure in your abdomen from gas
 diarrhea
 nausea
 throwing up

Alcohol
4. Alcohol
Drinking alcohol in moderation, or about one drink per day, normally doesn’t cause stomach
pain. But drinking too much alcohol at one time or over a long period of time can cause your
stomach lining to become inflamed. Long-term inflammation can lead to bleeding.

Drinking too much can also cause conditions such as:

 gastritis, or stomach inflammation

 pancreatitis, or inflammation of the pancreas
 liver disease

These conditions can all cause epigastric pain, too.

Check out: Gastritis diet: What to eat and what to avoid »

Overeating
5. Overeating
When you eat too much, your stomach can expand beyond its normal size. This puts a lot of
pressure on the organs around it. This pressure can cause pain in your gut. It can also make it
hard to breathe because your lungs have less room to expand when you inhale.

Overeating can also cause stomach acid and contents to back up into your esophagus. This can
cause heartburn and acid reflux. These conditions can make the epigastric pain that you feel after
eating much worse.

If you have an eating disorder related to binge eating, repeated vomiting after eating can also
cause epigastric pain.

Learn more: Identifying gallbladder problems »

Hiatal hernia
6. Hiatal hernia
A hiatal hernia happens when part of your stomach gets pushed up towards your diaphragm
through the hole that the esophagus passes through, which is called the hiatus.

Hiatal hernias don’t always cause pain or discomfort.

Common symptoms of a hiatal hernia can include:

  indigestion
 burning feeling in your chest
 irritated or sore throat
 burping loudly

Esophagitis
7. Esophagitis
Esophagitis happens when your esophagus lining becomes inflamed. Common causes include
acid coming back up from your stomach, allergies, infection, or chronic irritation from
medications. If you don’t treat it, over time esophagitis can eventually lead to scarring on your
esophagus lining.

Common symptoms of esophagitis include:

 burning in your chest or throat

 abnormal acidic taste in your mouth
 coughing
 having trouble swallowing or having pain when swallowing

Gastritis
8. Gastritis
Gastritis happens when the lining of your stomach (mucosa) becomes inflamed due to a bacterial
infection, an immune system disorder, or ongoing damage to your stomach. It can be acute and
last for only a brief time, or it can be chronic, lasting for years or more if you don’t get treatment.

Common symptoms of gastritis can include:

 pain or discomfort in your upper body or chest

 nausea
 vomiting, or throwing up blood or something that looks like coffee grounds
 passing black stool

Peptic ulcer disease

9. Peptic ulcer disease
Peptic ulcer disease happens when the lining of your stomach or small intestine gets damaged
due to a bacterial infection or by taking too much of certain medications, such as nonsteroidal
anti-inflammatory drugs (NSAIDs) for pain relief.
Common symptoms of peptic ulcer disease can include:

 nausea
 vomiting
 feeling easily full
 stomach pains that food can make better or worse
 signs of bleeding that can include tiredness, paleness, or shortness of breath

Barrett’s esophagus
10. Barrett’s esophagus
Barrett’s esophagus happens when the tissue that lines your esophagus starts to become more
like the tissue lining your intestines. This is known as intestinal metaplasia. This condition
requires close follow-up. Unchecked, Barrett’s esophagus can lead to cancer of the esophagus.
GERD, smoking, consuming alcohol, and obesity are also risk factors for this type of cancer.

This condition doesn’t have any unique symptoms of its own. If it happens because of GERD,
you may have symptoms such as:

 throat soreness or hoarseness

 abnormal acidic taste in your mouth
 burning in your stomach
 heartburn
 having trouble swallowing

Gallbladder inflammation or gallstones

11. Gallbladder inflammation or gallstones
Epigastric pain can develop when your gallbladder becomes inflamed as gallstones block the
opening of your gallbladder. The condition is known as cholecystitis. This can be painful and
may require hospitalization or surgery.

Common symptoms of gallbladder inflammation can include:

 not having an appetite

 intense pain around your gallbladder (upper right side of your stomach)
 nausea and vomiting
 bloating and gas
 high fever
 clay-colored stools
 skin that looks yellow (jaundice)
In pregnancy
12. Epigastric pain in pregnancy
Mild epigastric pain is common while you’re pregnant due to the pressure that your growing
pregnancy puts on your abdominal area. It’s also common because of the changes in your
hormones and your digestion. You may also experience frequent heartburn while you’re
pregnant.

However, significant epigastric pain in pregnancy is sometimes a symptom of a serious condition

known as preeclampsia. It requires close monitoring by your doctor and can become life-
threatening if severe. You’ll require close observation, blood pressure checks, blood tests, and
urine tests to rule this out as a cause of epigastric pain.

Treatment
Treatment options
Treatment for epigastric pain depends on the cause. If your pain is a result of your diet or
overeating, your doctor may recommend that you change your diet or lifestyle.

This may include exercising for about 30 minutes each day or eating healthier foods. Eating
foods like ginger and taking vitamin B supplements may help relieve symptoms like nausea and
throwing up.

If the pain is a result of taking certain medications, such as NSAIDs, your doctor may tell you to
stop taking these medications and help you find another way to manage pain. Your doctor may
recommend antacids or even acid blocking medicines to relieve your pain.

If an underlying condition such as GERD, Barrett’s esophagus, or peptic ulcer disease is causing
your epigastric pain, you may require antibiotics as well as long-term treatment to manage these
conditions. Treatment may last for months or even the duration of your life, depending on the
cause.

See your doctor

When to see your doctor
See your doctor right away if your epigastric pain is severe, ongoing, or interfering with your
daily life.

You should go to the emergency room if you have any of the following symptoms:
  trouble breathing or swallowing
 throwing up blood
 blood in your stool or black, tarry stool
 high fever
 chest pain
 difficulty breathing
 passing out

You should also see your doctor if your symptoms last for more than a few days without getting
any better with over-the-counter or home treatments. Many causes of epigastric pain can easily
be treated, including chronic conditions. Seeing your doctor as soon as you notice epigastric pain
that isn’t going away can help you relieve your symptoms and get any underlying conditions
under control.

 Acute cholecystitis. (2016).

15. esr

https://labtestsonline.org/tests/erythrocyte-sedimentation-rate-esr

16. occult stool

https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=fecal
_occult_blood

17. clo test

http://trimed.com.au/clotest/

18. gastroscopy

https://www.nhs.uk/conditions/gastroscopy/