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Mædica - a Journal of Clinical Medicine

MAEDICA – a Journal of Clinical Medicine


2013; 8(1): 68-74

E DITORIALS

Functional Dyspepsia Today


Theodor Alexandru VOIOSUa,b; Roxana GIURCANa; Andrei Mihai VOIOSUa;
Mihail Radu VOIOSUa,b
a
Department of Gastroenterology, Colentina Clinical Hospital, Bucharest, Romania
b
“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

ABSTRACT
Functional dyspepsia (FD) is a disorder presenting with symptoms such as postprandial fullness,
early satiety or epigastric pain. Although there is a 10 to 30% reported prevalence worldwide, there is
currently no clear explanation of the pathophysiology behind this condition. Motility disorders, visceral
hypersensitivity, acid disorders, Helicobacter pylori infection or psychosocial factors have all been re-
ported to play a part in the pathophysiology of FD. The diagnosis of FD is one of exclusion, based on the
Rome III criteria. The main therapeutic modalities include lifestyle changes, eradicating Helicobacter
pylori infection and treatment with either proton pump inhibitors, prokinetics or antidepressants.

INTRODUCTION field in the last decades. A variety of theories


have been proposed in the attempt to better

D
yspepsia is a clinical syndrome understand the pathopysiological mechanisms
which comprises a series of behind FD, but none have been conclusively
symptoms such as postprandial proven.
fullness, early satiety, or epigas- There are currently five main theories re-
tric pain, symptoms which can garded as possible explanations for FD symp-
accompany a number of gastrointestinal disor- toms and, while it now seems unlikely that any
ders. Although functional dyspepsia (FD) is di- one of them can account for the entire disease
agnosed in more than 60% of patients com- burden on its own, they each merit an individ-
plaining of these symptoms, the diagnosis ual discussion of pathophysiological mecha-
remains one of exclusion (1) after structural di- nism and its implications in FD treatment.
sease (such as peptic ulcer, esophagitis or diges-
tive malignancy) has been ruled out. 1. Motility disorders
Large studies have shown a 10-30% preva- Altered motility of the GI tract is an appar-
lence of FD worldwide, highlighting the impor- ently simple and elegant explanation for the
tance of FD as a healthcare issue (2). whole spectrum of FD symptoms, from epigas-
tric pain to early satiety, nausea and belching.
Pathophysiology According to some researchers, delayed
The cause of functional dyspepsia remains gastric emptying was present in 25-40% of pa-
unknown despite a great body of work in this tients with functional dyspepsia and it was as-

Address for correspondence:


Theodor Alexandru Voiosu, Colentina Clinical Hospital, Stefan cel Mare Road, no. 19-21, E Pavilion, Department of Gastroenterology,
medical practice no.1. Bucharest, Romania.
E-mail: theodor.voiosu@yahoo.com

Article received on the 22nd of November 2012. Article accepted on the 15th of January 2013.

68 Maedica A Journal of Clinical Medicine, Volume 8 No.1 2013


FUNCTIONAL DYSPEPSIA TODAY

sociated with postprandial satiation, nausea Increased sensitivity to lipids in the duodenum
and vomiting (3). was one of the first investigated pathways in FD
Ultrasound, barostat and single photon (10).
emission tomography studies demonstrated Other studies focused on the role of me-
impaired accommodation, an abnormal distri- chanic stimulation of gastric and duodenal re-
bution of ingested food in the stomach, with an ceptors. Results of gastric barostat studies have
increased proportion of the food being distrib- shown that patients with functional dyspepsia
uted in the antrum compared to the proximal have a lower sensitive threshold to the disten-
portion of the stomach. The impaired accom- sion of the barostat inside the proximal regions
modation of the stomach is caused by a vaso- of the stomach and the duodenum. This gastric
vagal reflex which requires nonadrenergic and hypersensitivity, defined as pain threshold 2
noncolinergic pathways (4). standard deviations below that of normal vol-
Recent studies suggest that delayed gastric untaries, is associated with postprandial epigas-
emptying leading to FD symptoms may be the tric pain and weight loss. Whether concomitant
result of an altered migrating motor complex Helicobacter pylori infection contributes to
(MMC) (5). There is also evidence linking the gastric hypersensitivity is a matter still open to
presence of HP infection to altered phase III debate (11).
gastric MMC (6), thus suggesting an interrela-
tion between these two pathogenic mecha- 3. Acid disorders
nisms of FD. Because FD symptoms are virtually indistin-
Another theory which is interesting also guishable from those of peptic ulcer disease
from a therapeutic viewpoint is the possibility (PUD) and because PPI treatment is a mainstay
that 5HT 3 receptors might be involved in the of FD treatment, many research groups have
abnormal distension of the stomach in response long advocated the role of abnormal gastric
to the perfusion of a fatty solution in the duo- and duodenal acid levels in FD. Studies have
denum (7). shown that acid secretion is normal in a major-
A disorder of the central or autonomous ity of dyspeptic patients but recent evidence
nervous systems has been studied as a possible suggests an abnormal acid clearance from the
mechanism for the impaired gastric accommo- duodenum as well as a decreased motor re-
dation and the antral hypomotility. There is sponse of the duodenum when acid is present.
some indirect evidence of a correlation be- pHmetry studies lasting 24 hours have shown
tween emotional and psychological factors and an increased exposure to acid after a meal, but
dyspeptic symptoms, via diminished vagal ac- no direct link between this exposure and dys-
tivity (8). peptic symptoms has been proven (12). These
Manometric studies have also shown antral observations have been recently confirmed by
hypomotility as well as numerous retrograde radiotelemetry pH monitoring over 48 hour
contractions from the duodenum towards the periods (13).
stomach. Unsuppressed phased contractility
increase parietal tension in the stomach which 4. Helicobacter pylori infection
is, in turn, perceived as postprandial discom- One of the main arguments behind the pos-
fort. This abnormality has been linked by some sible role of Helicobacter pylori (HP) infection
researchers with Helicobacter pylori infection in FD is derived from clinical experience, with
(9). a systematic review showing the positive im-
Despite the continued development of so- pact of HP eradication on FD symptoms (14)
phisticated methods allowing the minute ex- with a NNT of 15 (15). However, there is con-
ploration of GI tract physiology, correctly quan- flicting data on this matter, with a systematic
tifying the motility patterns of normal and FD review of studies striving to prove a causal rela-
patients is still proving a major obstacle in pro- tion between Helicobacter pylori infection and
viding adequate support for this theory. functional dyspepsia were inconclusive; a
modest relationship seems to exist but evi-
2. Visceral hypersensitivity dence is lacking to support an important role of
Some of the earliest studies in FD suggested HP infection in patients with functional dys-
a role for altered visceral sensitivity as an im- pepsia (16).
portant mechanism for dyspeptic symptoms.

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FUNCTIONAL DYSPEPSIA TODAY

5. Psychosocial factors tional symptoms such as nausea and belching


There has been a longstanding interest in may be present. Patients complaining of heart-
the role of psychological factors in the onset burn as a main symptom will usually receive a
and symptom severity in FD. Studies have es- GERD diagnosis, although there is probably an
tablished that psychosocial stressors influence important overlap between GERD and FD (22).
FD symptoms (17) and that depressive mood The lack of sensitivity and specificity of the clin-
and altered quality of life were more frequent ical diagnosis of FD has been highlighted by a
among FD and FD and IBS overlap patients clinical trial, which showed that only endosco-
(18). However, antidepressant treatment in FD, py was capable of correctly differentiating be-
the next logical step in this pathophysiological tween peptic ulcer disease, esophagitis and FD
chain, has been disappointing so far, raising (23).
questions over the validity of this particular ap- While the continued development of func-
proach to FD (19). tional explorations tests has allowed for a more
refined exploration of the physiology of the GI
6. Allergic disorders tract, no correlation has been found between
Recently, the role of various allergens has impaired mechanisms and FD symptoms as
been studied in both FD and IBS, with studies had been previously suggested (24). Due to the
showing an increase in the prevalence of food imprecise nature of its symptoms, functional
allergies (e.g.: eggs, soybeans) in FD and IBS dyspepsia has been defined using a set of peri-
patients (20). Furthermore, pathological studies odically revised diagnostic criteria. The Rome
have shown eosinophilia in the mucosa of FD III criteria, published in 2006, are the most
patients, but its relationship to food allergens commonly employed. They consist of one or
still needs further evaluation (21). more of the following symptoms (25): bother-
some postprandial fullness, early satiety, epi-
Symptoms and diagnosis gastric pain, epigastric burning and no evidence
of structural disease (including at upper endos-
The cardinal symptoms of FD are epigastric
copy) that is likely to explain the symptoms.
pain, postprandial discomfort often described
The criteria must be fulfilled for the last 3
as postprandial fullness and early satiety. Addi-
months with symptom onset at least 6 months
prior to diagnosis.
A. Postprandial Distress Syndrome The older Rome II criteria which classified
Diagnostic criteria* must include one or both of the following: functional dyspepsia as ulcer-like, dysmotility-
Bothersome postprandial fullness, occurring after ordinary-sized like and nonspecific were abandoned in favor
meals, at least several times per week of the more precise Rome III (22) criteria based
Early satiety that prevents finishing a regular meal, at least several
on the four cardinal symptoms already present-
times per week
Supportive criteria ed. According to the dominant presenting
Upper abdominal bloating or postprandial nausea or excessive symptom, two subtypes of FD were defined as
belching can be present follows (Table 1):
Epigastric pain syndrome may coexist
B. Epigastric Pain Syndrome
Therapy of functional dyspepsia
Diagnostic criteria* must include all of the following:
Pain or burning localized to the epigastrium of at least moderate The heterogeneous nature of the functional
severity, at least once per week dyspepsia patient population makes it difficult
The pain is intermittent
to have a representative study group, which is
Not generalized or localized to other abdominal or chest regions
Not relieved by defecation or passage of flatus one of the reasons that the results of drug trials
Not fulfilling criteria for gallbladder and sphincter of Oddi (26) tend to be discordant. During the past decades,
disorders many trials have addressed the problem of FD
Supportive criteria therapy, with unsatisfying and sometimes con-
The pain may be of a burning quality, but without a retrosternal tradictory results.
component
The pain is commonly induced or relieved by ingestion of a meal,
but may occur while fasting Lifestyle alteration
Postprandial distress syndrome may coexist General measures such as smaller, more fre-
TABLE 1. Functional dyspepsia subtypes quent meals, avoiding caffeine, alcohol,
* Criteria fulfilled for the last 3 months with symptom onset at least 6 months NSAIDs, fatty or spicy meals, seem in order, al-
prior to diagnosis

70 Maedica A Journal of Clinical Medicine, Volume 8 No.1 2013


FUNCTIONAL DYSPEPSIA TODAY

though there is little evidence supporting their such as paroxentine, valexetine, were no more
use (27). effective than placebo on improving symp-
toms, according to results of a randomized
Pump proton inhibitor placebo-controlled trial (34).
Two regimens of antisecretory therapy were The role and the mechanism of antidepres-
proposed: „step-up” (e.g., start with antacids, sants in functional dyspepsia remain unsettled.
then H2-blockers and then proton pump in-
hibitors) or „step-down”. A metanalysis com- Management of functional dyspepsia
paring these two strategies has showed similar
From the insufficient understanding of the
success rate, but with higher costs for step-
pathogenic mechanisms of functional disorders
down approach at six-months (28).
stems, to the difficulty of setting up diagnostic
Several placebo-controlled trials had the
and therapeutic guidelines. Furthermore, there
same results regarding the efficacy of PPI, a
is a logical incongruity between the diagnostic
meta-analysis finding an NNT of 10 and a rela-
criteria for FD and its management. Although a
tive risk reduction of 13%, without difference
diagnosis of FD requires the absence of any
between doses of PPIs (29). However, the relief
structural disease, including at endoscopy,
of symptoms was greatest in patients with ul-
management guidelines support empiric anti-
cer-like and reflux-like symptoms, but not in
secretory or prokinetic therapy in patients with
those with dysmotility-like symptoms or un-
suspected FD who show no alarm symptoms
specified dyspepsia.
(35). Endoscopy is recommended only in those
cases where alarm symptoms are present or pa-
H2-receptor antagonists (H2RA)
tients are non-responders to at least 4 weeks of
Many trials, which probably included GERD
empiric therapy. As such, a vast majority of FD
patients, found a significant benefit and a rela-
patients will most likely receive treatment with-
tive risk reduction of 23% with a number to
out undergoing endoscopy for diagnosis confir-
treat of 7, but better quality trials showed a low
mation.
efficacy for H2RA therapy (30).
The first step in evaluating any patient is his-
tory taking and physical examination, which
Prokinetics
can help suggest either a structural or a func-
Prokinetics act on three different types of
tional disorder. Routine lab tests (e.g.: blood
receptors in order to enhance gastric motility.
count) can also be helpful in an initial workup
These drugs might help alleviate satiation, ab-
of the patient.
dominal distention and nausea, but the link be-
In addition, the physician needs to pay at-
tween symptom relief and improved gastric
tention to the so-called „alarm symptoms”,
emptying is not yet proven (31).
which increase the likelihood of a structural
Several studies have symptom relief for cis-
disease (Table 2). Any of these signs and symp-
apride and domperidone, with a reduction in
toms requires an endoscopic study to assess a
relative risk of 50% (32). Cisapride, however,
possible malignancy. The American Society of
has been withdrawn because of safety con-
Gastroenterology (ASGE) guidelines emphasize
cerns and domperidone is not widely available.
Metoclopramide may also be effective, but
is associated with several potential side effects, Alarm symptoms
particularly with long-term use. Itopride, a do- Age > 50 yrs
pamine D2 antagonist, was effective in a phase Family history of digestive malignancy
III multicenter trial; the suggested mechanism Involuntary weight loss
of action being its effect on gastric accommo- Unexplained anemia or iron deficiency
dation and hypersensitivity (33). Progressive dysphagia
Hematemesis
Antidepressants Odinophagia
If initial treatment with IPPs or prokinetics Recurrent vomiting
fails, antidepressants can be employed, in low- Palpable tumor or lymphadenopathy
er doses than required in the treatment of de- Jaundice
pression. Tricyclic antidepressants as well as Previous gastric surgery
selective serotonine reuptake inhibitors (SSRI) TABLE 1. Alarm symptoms

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FUNCTIONAL DYSPEPSIA TODAY

the fact that the positive predictive value of copy (40-42) has the advantage of excluding
these symptoms is low (11%). However, their peptic ulcer, esophagitis and cancer as causes
negative predictive value in excluding gastroin- of dyspepsia. A meta-analysis of nine studies
testinal malignancy is very high, approximately with 5389 patients showed that the most com-
97% (36). This is the logical consequence of the mon finding in patients with dyspeptic symp-
fact that only 2% of dyspeptic syndromes are toms was erosive esophagitis (pooled preva-
caused by esophageal or gastric cancer, 30 lence 13%), though the prevalence was much
times fewer than functional dyspepsia (37). lower when dyspepsia was defined using the
Conversely, the presence of alarm symptoms Rome criteria (6 %) (43).
provides reasonable guidance, and has been In addition, clinical trials show that simply
included in consensus recommendations on being subjected to an endoscopic study in-
functional dyspepsia management. creases the patient’s level of satisfaction and
Excluding gastroesophageal reflux disease confidence (44). Supporters of empiric therapy
(GERD) as the cause of dyspeptic symptoms is argue that a low incidence of cancer (less than
also of paramount importance because GERD 2% of dyspeptic patients) and the high costs in-
has a different treatment and prognosis and re- curred by endoscopy should preclude upper
quires a particular management strategy involv- digestive endoscopy as a first step in investigat-
ing long-term proton pump inhibitor therapy ing these patients. Accordingly, patients under
(IPP) and active surveillance for reflux esopha- 45-50 years of age without any alarm symp-
gitis, Barrett’s esophagus as well as esophageal toms could be treated empirically with minimal
cancer. Many GERD patients are diagnosed risks (45), endoscopic studies being reserved
with functional dyspepsia because of the lack for those patients who are nonresponsive to
of structural abnormalities in endoscopic stud- 6-8 weeks of therapy. However, given that
ies and the great variety of symptoms of func- many patients do not achieve full symptomatic
tional dyspepsia (including heartburn) which in relief with medical therapy, requiring further
turn has lead to confusing results in many clini- investigations, it seems more prudent to per-
cal trials (38). form endoscopy in the initial workup. If this
A drug-induced dyspepsia must be also tak- initial endoscopic study is normal, endoscopy
en into account, especially nonsteroidal anti- will not be repeated unless alarm symptoms
inflammatory drugs (NSAIDs) commonly asso- develop.
ciated with dyspepsia. In this case, the offending The American Gastroenterology Associa-
agent should be discontinued, if possible, or a tion’s guidelines from 2005 also suggest that
proton pump inhibitor can be added (PPI) (39). endoscopy should be performed in patients
Patients on long term NSAID treatment can be with dyspepsia who have alarm symptoms or
considered at risk for peptic ulcer disease and those without alarm symptoms who are ≥55
the physician should decide whether endosco- years of age (46). The authors point out that in
py is warranted from the first visit. some regions where cancer incidence is higher
The optimal approach for a patient with un- (such as Alaska), lower age thresholds are ap-
investigated dyspeptic symptoms is far from be- propriate, for example 45 years rather than 55
ing decided. Several strategies for the manage- years of age. Patients who receive medication
ment of these patients have been proposed, should be evaluated for symptomatic improve-
but several systematic reviews have failed to ment at approximately eight weeks.
settle the dispute.
The options taken into discussion were: 2. Empiric antisecretory therapy
1. Prompt endoscopy The empiric antisecretory therapy has ad-
2. Empiric antisecretory therapy vantages and disadvantages, according to con-
3. Noninvasive testing for Helicobacter flicting results of studies. Many patients can
pylori, followed by treatment or endoscopy if have a favorable symptomatic response, but
positive (test-and-treat strategy) this does not exclude a malignant gastric ulcer
and it can delay the diagnosis. Also, the recur-
1. The role of endoscopy in FD rence of the symptoms is common after one
The most debated problem in the manage- year (47) and the lack of H. pylori eradication
ment of FD, as already shown above, is the role increases the risk of ulcer recurrence.
of an initial upper digestive endoscopy. Endos-

72 Maedica A Journal of Clinical Medicine, Volume 8 No.1 2013


FUNCTIONAL DYSPEPSIA TODAY

3. Test and treat strategy


The relationship between Helicobacter py-
lori infection and peptic ulcer disease is well
known but H. Pylori infection alone can ac-
count for a minority of cases of chronic dyspep-
sia. For this reason, the consensus of European
H. Pylori Study Group (March 2005) suggested
a „test-and-treat” approach for patients less
than 45 years old with persistent dyspepsia (a
remark is made for the age cutoff, which may
vary with the prevalence of gastric cancer in
different countries). Another conclusion was
that, in countries with low prevalence of H. py-
lori infection (<20%), the empirical therapy
with PPI is preferred to the test and treat strat-
egy (48).
Among the noninvasive studies the most
widely used in managing functional dyspepsia
are the 13C-urea breath test and the stool anti-
gen test for Helicobacter pylori (HP), the IgG FIGURE 1. Treatment algorithm for FD.
serology being reserved for the cases where
pretest probability is high, followed by a confir- effectiveness has been validated by clinical tri-
mation by one of the methods mentioned als. For the time being, use of a PPI or/and a
above.  prokinetic for a minimum of 4 to 8 weeks
CONCLUSIONS seems the best option available (Figure 1). New
drugs such as antidepressants might be of use

A s long as the mechanisms of disease in-


volved in functional dyspepsia are not fully
understood we cannot hope for an adequate
in treatment failures but further research is
needed in order to provide better care for FD
patients.
treatment for FD. Consequently, physicians
must rely on empiric therapies, choosing those Conflict of interest: none declared.
drugs that have a good safety profile and whose Financial support: none declared.

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