Review
Digestion 2018;97:6–12
DOI: 10.1159/000484029
New Medical Approach to Functional
Dyspepsia, from Core Symposium 3, Japan
Gastroenterological Association 2015–2017
Hidekazu Suzuki
Fellowship Training Center and Medical Education Center, Keio University School of Medicine, Tokyo, Japan
Keywords
Functional dyspepsia · Helicobacter pylori · Overlap
syndrome · Treatment
Abstract
In the annual meeting of the Japan Gastroenterological As-
sociation (JGA), the scientific organizing committee selected
the serial topics for the core symposium. One of the core
symposia held during 2015–2017 was entitled “New medical
approach to functional dyspepsia (FD).” In 2015, the subtitle
of this symposium was “Helicobacter pylori gastritis and FD.”
In 2016, the subtitle of this symposium was “overlap with
other functional GI disorders.” In 2017, the subtitle was “ther-
apeutic approach to FD.” During these 3 years, a total of 24
presentations were included in Core Symposium 3 and deep
and intensive discussions were carried out.
© 2018 S. Karger AG, Basel
Introduction
The diagnosis “functional dyspepsia” (FD) has been
broadly accepted in the field of gastroenterology even in
Japan after the Rome III publication in 2006 [1]. In the
© 2018 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/dig
Published online: February 1, 2018
revised Rome IV publication [2], a minor modification
of the Rome III description for FD diagnosis has been
added. According to our previous web survey [3], the
prevalence of FD was 7.0%, including postprandial dis-
tress syndrome (PDS) alone in 4.7% (67.3% of FD), epi-
gastric pain syndrome (EPS) alone in 0.8% (11.0% of
FD), and overlap of PDS and EPS in 1.5% (21.7% of FD),
also suggesting a lower prevalence of overlap in a popu-
lation-based study in Japan. Our another web survey in
Japan [4] also showed that the prevalence of FD was
8.0%, including PDS alone in 4.8% (61.0% of FD), EPS
alone in 0.8% (10.3% of FD), and overlap of PDS and
EPS in 2.3% (28.8% of FD). These results suggest that
the prevalence of PDS in the general population is high-
er than that in EPS and that the overlap of PDS with EPS
is less than that in a hospital-based tertiary care popula-
tion [5].
In Japan, the national health insurance system ap-
proved the diagnostic name of FD for the first time in
2013 and the prokinetic agent acotiamide for the treat-
ment of FD, especially for PDS [2, 6, 7]. In the reflection
to such a background, the core symposia for FD from
2015 to 2017 were fruitful and successful with a message
of the need to continue diagnostic and therapeutic devel-
opment in this medical field.
Hidekazu Suzuki, MD, PhD, FACG, AGAF, RFF
Professor, Medical Education Center, Keio University School of Medicine
35 Shinanomachi, Shinjuku-ku
Tokyo 160-8582 (Japan)
E-Mail hsuzuki.a6 @ keio.jp
 Core Symposium 3 of the 11th Annual Meeting of
the Japan Gastroenterological Association (2015)
The role of Helicobacter pylori infection in upper-GI
diseases, especially in Japan, cannot be ignored [8]. In
the 11th annual meeting of the Japan Gastroenterologi-
cal Association (JGA), the subtitle of Core Symposium 3
was “H. pylori gastritis and FD” chaired by Prof. Hiroto
Miwa of Hyogo Medical University and myself (Fig. 1).
At the beginning of this symposium, Prof. Mototsugu
Kato of Hokkaido University gave the keynote lecture
about the novel disease concept of H. pylori-associated
dyspepsia (HpD) [9–11] that was recently defined at the
Kyoto Global Consensus Meeting for H. pylori infection
[12, 13]. In this international consensus meeting chaired
by Prof. Kentaro Sugano [12], all 24 statements for 22
clinical questions after extensive modifications and
omission of one clinical question in terms of post-infec-
tious dyspepsia related to H. pylori infection were
achieved with a consensus level >80%. At this consensus
meeting, a new category of HpD together with a diag-
nostic algorithm was proposed. If symptomatic remis-
sion continues over 6 months or longer after H. pylori
eradication, the symptoms of dyspepsia are due to H.
pylori-infected gastritis and the condition is defined to
diagnose as HpD [2, 9, 10]. In line with this Kyoto con-
sensus meeting, the new Rome IV chapter of FD [2]
clearly described this novel disease entity of HpD that is
thought to be different from FD. In the flowchart of di-
agnostic and therapeutic approaches in the Japanese So-
ciety of Gastroenterology for FD [14] and the Rome IV
[2] guidelines, H. pylori testing and treatment were de-
scribed before the diagnosis of FD and then eradication
therapy was administered at the beginning of all other
drug treatments. This means that HpD is a separate and
distinct disease entity from FD.
Host genetic diversity is a key pathogenetic factor re-
lated to dyspeptic symptoms. For the assessment of
pathogenesis of FD, neurochemical serotonin (5-HT) is
an important signalling molecule for gastrointestinal mo-
tor and sensory functions. Arisawa et al. [15] extensively
explored the host genetic side of FD patients, especially of
those with H. pylori-negative pure FD, clarified the asso-
ciation between FD and SLC6A4 polymorphisms and in-
vestigated rs5981521 (C>T) in pri-microRNA 325. Ac-
cording to their study [15], the number of rs5981521 T
alleles was significantly correlated with an increased risk
for FD (OR 1.45; 95% CI 1.05–1.98; p = 0.022) and the TT
homozygote was more closely associated with the risk for
FD (OR 3.01; 95% CI 1.41–6.42; p = 0.0043). The TT ho-
New Medical Approach to FD, from Core
Symposium 3, JGA 2015–2017
mozygote also significantly increased the risk for both
EPS and PDS (OR 3.04; 95% CI 1.25–7.42; p = 0.014 and
OR 3.05; 95% CI 1.14–8.13; p = 0.026 respectively). Based
on the exclusion of the effects of H. pylori infection, they
showed that H. pylori-negative TT homozygotes were at
greater risk for FD (OR 8.37; 95% CI 1.78–39.5; p  =
0.0072). The transmembrane serotonin transporter (5-
HTT; SLC6A4) governs 5-HT reuptake. In subjects with
the SLC6A4 5′-untranslated region wild homozygote, the
number of rs5981521 T alleles was significantly correlat-
ed to an increased risk for FD (OR 1.45; 95% CI 1.03–2.04;
p = 0.033). Of note, in subjects who were SLC6A4 3′-un-
translated region mutant carriers, the number of
rs5981521 T alleles was also significantly correlated with
an increased risk for FD (OR 2.07; 95% CI 1.08–3.98; p =
0.029), suggesting that the genetic polymorphism pri-mi-
croRNA 325 is associated with FD and interacts with
­SLC6A4 polymorphisms in increasing susceptibility to
FD in Japanese patients [15]. They also examined the as-
sociation between FD and SCN10A non-synonymous
polymorphisms (2884 A>G, 3218 C>T, and 3275 T>C)
that encode the tetrodotoxin-resistant sodium channel
1.8/sensory-neuron specific on C-fibres [16] and con-
cluded that genetic polymorphisms of SCN10A are close-
ly associated with FD (both EPS and PDS) in Japanese
H. pylori-negative subjects [16].
Gastroduodenal motility might be a key factor for
modifying dyspeptic symptom and linking with the
pathogenesis of FD [17–19]. Using a novel drinking-
ultrasonography test [20] to assess gastric motility and
sensory function of FD patients, Hata et al. [21] exam-
ined 20 healthy volunteers and 26 successive FD pa-
tients according to the Rome III criteria and showed
that the mean cross-sectional area of the fornix after the
intake of 800 mL of water was significantly lower in the
FD group than in the control group. In addition, in the
FD group, marked abdominal symptoms developed im-
mediately after the initiation of water intake and Visual
Analogue Scale (VAS) scores differed significantly (p <
0.01) between the control and FD groups. Their novel
method revealed abnormalities in gastric accommoda-
tion and sensation in patients with FD. They also showed
by drinking-ultrasonography that hypersensitivity be-
fore H. pylori eradication was significantly improved af-
ter the eradication in young subjects (unpublished
data).
Genetic diversity in the H. pylori strain side would be
important for symptom generation. Our group is very in-
terested in the characteristics of H. pylori strain diversity
that contribute to the generation of dyspeptic symptoms
Digestion 2018;97:6–12 7
DOI: 10.1159/000484029
 2015
H. pylori gastritis and FD
- H. pylori -associated
dyspepsia (HpD)
- Host genetic diversity
(SLC6A4, pri-miR-325,
SCN10A)
- H. pylori strain diversity
- Gastroduodenal
motility
- Endoscopic gastritis
and dyspeptic
symptom
- Aspirin user
Fig. 1. JGA Core Symposium 3 (2015–
- Response to PPI
2017): new medical approach to functional
dyspepsia.
in patients with HpD. In 2015, Matsuzaki et al. at Keio
University talked about the preliminary results of a study
of the association between napA mutation status in H.
pylori and the presence of chronic dyspeptic symptoms
(unpublished data).
Naito et al. [22] conducted a case-control study to
identify the differences in the endoscopic findings and
dyspeptic symptoms using the Frequency Scale for the
Symptoms of Gastroesophageal Reflux Disease (GERD)
questionnaire [23] between 68 patients after H. pylori
eradication and 68 age- and gender-matched controls
without H. pylori infection in a routine health check-up.
The incidence of advanced atrophic gastritis was 69% in
H. pylori-eradicated patients and 0% in H. pylori-unin-
fected patients. On the other hand, the incidences of su-
perficial gastritis/fundic gland polyps were 0/1.5% and
32.3/38.2% in the H. pylori-eradicated and H. pylori-
uninfected groups respectively. Despite such significant
differences in gastric endoscopic findings, no differenc-
es in dyspeptic symptoms were seen in these 2 groups
[22].
Kamada et al. [24] previously compared the efficacy
of different doses of proton pump inhibitors (PPIs) and
different administration methods in H. pylori-negative
dyspeptic patients. They showed in their study that
symptom improvement rates after 4 weeks of treatment
were 65.6% (40/61) in the 20 mg omeprazole group,
47.2% (34/72) in the 10 mg omeprazole group, and 50.0%
(31/62) in the on-demand group. The omeprazole 20 mg
group exhibited a significantly higher improvement rate
(p  = 0.034) than the omeprazole 10 mg group. The
omeprazole 20 mg group showed significant improve-
ments in regurgitation, postprandial fullness, vomiting,
8 Digestion 2018;97:6–12
DOI: 10.1159/000484029
2016 2017
Overlap with other FGIDs Therapeutic approach to FD
- FD and GERD (NERD) - Efficacy of prompt
overlap endoscopy
- FD and early chronic - H. pylori eradication
pancreatitis overlap - Anti-secretory agents (PPIs
- FD and other FGIDs or PCAB)
overlap - Acotiamide
- Delayed or rapid gastric - Kampo (rikkunshito etc.)
emptying (duodenal
brake, gender, exercise…)
- Combination therapy of
anti-secretory agents
with prokinetics
and bloating compared with the omeprazole 10 mg group
[24]. At Core Symposium 3 in 2015, they explored the
relationship between H. pylori infection and dyspeptic
symptom generation in a young adult population and
demonstrated that a more severe decrease in quality of
life was seen in H. pylori-negative individuals than in
H. pylori-positives.
In this symposium, other speakers talked about gastric
mucosal lesion formation assessed by the Lanza score
[25] as well as about the improvement of dyspeptic symp-
toms and quality of life by eradication.
Core Symposium 3 of the 12th Annual Meeting of
the JGA (2016)
In the 12th annual meeting of the JGA in 2016, the
subtitle of Core Symposium 3 was “Overlap of FD with
other functional gastrointestinal disorders (FGIDs)”
chaired by Prof. Atsushi Nakajima of Yokohama City
University and myself. In this symposium, overlap among
FGIDs was mainly discussed (Fig. 1).
Even in a new Rome IV definition, it is very difficult
to separate FD from GERD. Especially, reflux symptoms
due to non-erosive reflux disease were difficult to isolate
from the epigastric burning sensation due to EPS. Dur-
ing maintenance PPI therapy, patients with GERD
sometimes complain of upper gastrointestinal symp-
toms other than heartburn. Kusano et al. [26] reported
that non-erosive reflux disease patients had significant-
ly higher dyspeptic symptom scores than erosive esoph-
agitis patients and often wished to change their PPI ther-
apy. On the other hand, they showed that dyspeptic
Suzuki
symptoms were significantly less common in subjects
with gastroptosis, suggesting that gastroptosis may pro-
tect against dyspeptic symptoms rather than causing FD
[27]. Their group also focused on cascade stomach [28]
and reported that it could be a factor that may contribute
to various functional gastrointestinal disorders such as
FD [29].
It is worth emphasizing that the duodenum and the
duodeno-gastric interaction (duodenal brake) could have
an important role in the pathophysiology of FD. Kusano
et al. [30] hypothesized that rapid rather than delayed
gastric emptying could be a cause of FD. In some patients
with PDS, they found a significant correlation between
PDS-related dyspepsia and accelerated gastric emptying
in the early postprandial period, suggesting that acceler-
ated gastric emptying was more important than delayed
gastric emptying. We recently reported the association
between the intensity of regular exercise and gastric emp-
tying to determine the effect of physical activity on dys-
peptic symptoms [31]. In this report [31], gastric empty-
ing was significantly faster in the low-intensity exercise
group than in the moderate-intensity exercise group. Al-
though the presence of loose stool and alcohol consump-
tion were also associated with the intensity of regular ex-
ercise, these variables were not confounders. These re-
sults suggest that since the intensity of regular exercise
was independently associated with gastric emptying in
healthy individuals, these baseline data should be consid-
ered in cases of optimal exercise intervention for the
treatment of FD [31].
For overlap syndrome between GERD and FD, anti-
secretory agents and/or prokinetics such as acotiamide
might be effective therapeutic options [32]. In the core
symposium of 2016, Takeuchi et al. [33] showed the add-
on effect of acotiamide to PPI for GERD and FD overlap
patients, suggesting the esophageal motility acceleration
by acotiamide [34].
SLC6A4 expression may be regulated by epigenetic
mechanisms. Tahara et al. [35] investigated the DNA
methylation status of the SLC6A4 gene in the gastric
mucosa of patients from FD because of its potential role
in dyspeptic symptoms. According to their study, the
methylation level of the promoter CpG islands was sig-
nificantly lower in patients with FD (p = 0.04). On the
other hand, the methylation level of the gene body
­non-CpG islands was significantly higher in patients
with FD (p  = 0.03). It will be interesting to explore
whether such a DNA methylation pattern of SLC6A4
would be changed in overlap cases of FD and other
FGIDs.
New Medical Approach to FD, from Core
Symposium 3, JGA 2015–2017
Determining the pathogenesis of FD is another impor-
tant way to elucidate the mechanism of gastric emptying.
In 2016, we reported that gastric emptying measured by
the 13C-acetate breath test was slower in women than in
men even among non-dyspeptic healthy cohorts. This
finding suggests that the standard values of the 13C-ace-
tate breath test should be modified to account for gender
differences [36]. For the assessment and diagnosis of FD,
especially in cases of overlap with other FGIDs, both age
and gender differences should be considered.
FD symptoms are sometimes indistinguishable from
those of chronic pancreatitis. However, in terms of over-
lap between FD and pancreatic diseases, there are not
enough data. Using endosonography, Hashimoto et al.
[37] recently examined whether EPS accompanied by
pancreatic enzyme abnormalities was associated with
early chronic pancreatitis as proposed by the Japan Pan-
creas Society [38]. Their study showed that 64% of EPS
patients with pancreatic enzyme abnormalities were di-
agnosed by endosonography as having concomitant early
chronic pancreatitis [37].
Core Symposium 3 of the 13th Annual Meeting of
the JGA (2017)
In the 13th annual meeting of the JGA (2017), the sub-
title of Core Symposium 3 was “Therapeutic approach to
FD” that was chaired by Prof. Takeshi Kamiya, Nagoya
City University and myself (Fig. 1).
To rule out organic disorders, prompt endoscopy [39]
should be considered the initial strategy for uninvesti-
gated dyspepsia in the background of the high prevalence
of H. pylori infection and gastric malignancy. Hongo et
al. [40] performed a prospective multicentre clinical
comparative study involving the randomized allocation
of open-label medications that compared the effective-
ness for FD of mosapride versus teprenone in Japan. In
this study, organic lesions were found in 90 (9%) of the
1,027 patients examined by endoscopy; among those
without any specific lesions on endoscopy, the gastroin-
testinal symptoms were resolved within 1 week after en-
doscopy in 264 (28%) patients, suggesting the impor-
tance of prompt endoscopy for the relief of dyspepsia. To
evaluate the appropriateness of prompt endoscopy as an
initial dyspepsia management strategy, we investigated
the organic lesion detection rates in Asian dyspepsia pa-
tients as well as the diagnostic accuracies of alarm fea-
tures and age thresholds for malignancy in a systematic
review and meta-analysis [39] and demonstrated that the
Digestion 2018;97:6–12 9
DOI: 10.1159/000484029
malignancy detection rate and proportion of young can-
cer patients were high among Asian dyspepsia patients,
suggesting that prompt endoscopy should be considered
the initial strategy for dyspepsia in Asian populations.
One speaker showed the correlation of H. pylori infec-
tion and endoscopic findings using Kyoto gastritis clas-
sification [41] in patients with dyspepsia, while the other
talked about the showed the symptomatic characteristics
of HpD by using self-reported questionnaires such as the
Gastrointestinal Symptom Rating Scale [3, 42] and Glob-
al Overall Severity and demonstrated the efficacy of H.
pylori eradication therapy for relieving dyspepsia (un-
published data).
The definition of PPI-resistant GERD should be mod-
ified after the launching of potent potassium-competi-
tive acid blockers such as vonoprazan [43–47], the evalu-
ation of other therapeutic agents for PPI-resistant GERD
as monotherapy and add-on therapy to PPI or potassi-
um-competitive acid blockers should be re-evaluated.
One speaker talked about the efficacy of ­hangeshashinto
for PPI-resistant reflux symptoms, while the other speak-
er talked about the efficacy of acotiamide for treating FD
and other FGIDs (unpublished data).
The efficacy of Japanese herbal medicine on FD is an-
other important field [48]. In 2017, our group summa-
rized the data of the Rikkunshito study and focused on the
difference between tertiary care hospitals and primary
clinics [49]. Using the dataset of the previously performed
randomized placebo-controlled trial to evaluate the effi-
cacy of rikkunshito, a Japanese herbal medicine, in pa-
tients with FD [49], they evaluated the predictive markers
of the efficacy of rikkunshito and found that a low baseline
plasma des-acyl ghrelin level [50] was associated with an
increased treatment efficacy of rikkunshito against FD,
but the same finding was not reported by the intervention
sites (tertiary hospitals or primary clinics) [51].
Conclusion
This study described a new treatment strategy for FD
referring to the revised Rome IV classification [2]. For FD,
only minor changes were introduced, mainly to improve
specificity. Among the major symptoms of FD, postpran-
dial fullness as well as epigastric pain, epigastric burning,
and early satiation should be “bothersome.” An investiga-
tion on the effect of meal ingestion on symptom generation
indicated that not only postprandial fullness and early sati-
ety but also epigastric pain, an epigastric burning sensation,
and nausea (not vomiting) may increase after meals [50].
H. pylori infection is considered a possible cause of dyspep-
sia if successful eradication leads to a sustained resolution
of symptoms for more than 6 months, and such status can
be termed HpD [52]. Prompt esophagogastroduodenosco-
py and H. pylori testing and treatment would be more ben-
eficial, especially in Asia, which has a high prevalence of
gastric cancer. Acotiamide, tandospirone, and rikkunshito
are the newly listed treatment options for FD.
Disclosure Statement
During the last 2 years, H.S. received scholarship funds for the
research from Otsuka Pharmaceutical Co., Ltd., EA Pharma Co.
and Tsumura Co., and received service honoraria from Astellas
Pharma Inc., AstraZeneca K.K., Otsuka Pharmaceutical Co., Ltd.,
Daiichi-Sankyo Co., Takeda Pharmaceutical Co., Ltd., Mylan EPD
Co., and Zeria Pharmaceutical Co., Ltd.
Funding Sources
The present study was supported by a Grant-in-Aid for Scien-
tific Research B (16H05291) from the Japan Society for the Promo-
tion of Science, a MEXT-Supported Program for the Strategic Re-
search Foundation at Private Universities (S1411003), and the
Princess Takamatsu Cancer Research.

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Suzuki