Arab Journal of Gastroenterology 20 (2019) 91–94

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Arab Journal of Gastroenterology

journal homepage: www.elsevier.com/locate/ajg

Original article

Duodenal lymphocytosis in functional dyspepsia

Annalisa Capannolo a,⇑, Stefano Necozione b, Dolores Gabrieli a, Fabiana Ciccone a,
Laura Sollima c, Loredana Melchiorri c, Angelo Viscido a, Giuseppe Frieri a
a
Gastroenterology Unit, Department of Life, Health, & Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
b
Clinical Epidemiology, Department of Life, Health, & Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
c
Pathology Unit, San Salvatore Hospital, 67100 L’Aquila, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Background and study aims: Functional dyspepsia is an exclusion diagnosis requiring different tests,
Received 8 January 2018 including endoscopy, often repeated over time. Duodenal biopsies are frequently resorted to, not rarely
Accepted 26 May 2019 revealing duodenal microscopic inflammation. Aim of the study is to confirm a previously supposed role
of antro-duodenal low-grade inflammation in functional dyspepsia, evaluating the frequency of duodenal
lymphocytosis, H. pylori infection and their association in a group of patients with functional dyspepsia
Keywords: compared to asymptomatic control subjects.
Functional dyspepsia
Patients and methods: A cross-sectional, observational study has been conducted screening all the
H. pylori
Duodenal lymphocytosis
patients who underwent duodenal biopsies during upper endoscopy, in a 30 months period. All the
Microscopic duodenitis patients without endoscopic lesions were analysed. The study group consisted of patients compatible
Bloating with the diagnosis of functional dyspepsia (Rome III criteria). The control group consisted of healthy
asymptomatic subjects in the population subjected to endoscopy. The presence of duodenal lymphocyto-
sis and of H. pylori infection in the two groups was evaluated.
Results: 216 patients were enrolled: 161 in the functional dyspepsia group and 55 as asymptomatic con-
trol group. The frequency of duodenal lymphocytosis was similar between cases and control groups
(25.47% vs 25.45%; p = 0.99), as well as H. pylori infection (26.71% vs 23.64%; p = 0.78). Duodenal lympho-
cytosis was significantly associated with functional dyspepsia only in H. pylori positive dyspeptic
patients (p = 0.047). 94% of the subjects with both lymphocytosis and H. pylori infection suffer from dys-
pepsia. Duodenal intraepithelial lymphocytosis is significantly associated with bloating (p = 0.0082).
Conclusions: In our cohort of dyspeptic patients, duodenal lymphocytosis is significantly associated with
bloating and the simultaneous presence of duodenal lymphocytosis and H. pylori infection is significantly
more prevalent than in control subjects.
Ó 2019 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Introduction into 2 sub-groups: postprandial distress syndrome (PDS) and epi-

Functional dyspepsia (FD) is defined, according to Rome criteria,
as the presence of symptoms thought to originate in the gastroduo-
denal region, in the absence of any organic, systemic, or metabolic
disease that could account for them [1]. Symptoms are various and
unspecific, ranging from mild discomfort to severe epigastric pain.
On the basis of the prevalent symptom of the patient, FD is divided
Abbreviations: FD, functional dyspepsia; PDS, postprandial distress syndrome;
EPS, epigastric pain syndrome; tTG, IgA tissue transglutaminase; IBS, irritable bowel
syndrome; IELs, intraepithelial lymphocytes.
⇑ Corresponding author at: Department of Life, Health, & Environmental Sciences,
University of L’Aquila, Piazzale S. Salvatore, L’Aquila 67100. Italy.
E-mail address: annalisacap@tiscali.it (A. Capannolo).
gastric pain syndrome (EPS), which can overlap. The prevalence
in the general population has been reported to be as high as 11–
15% [2,3], three times more than organic dyspepsia [4], with a great
impact both on the healthcare system [5] and the patient’s quality
of life [6–8].
Diagnosis requires the symptoms to be bothersome, to have
been recurrently present over the previous 3 months, with onset
at least 6 months before [9]. It is an exclusion diagnosis requiring
various tests, including endoscopy with biopsies, often repeated
over time [10–12]. Duodenal biopsies, sometimes performed in
FD [13], can reveal duodenal microscopic inflammation [14–18].
Several findings were reported, for example, the presence of H.
pylori derived microscopic duodenitis in dyspeptic patients repre-
sents a predictive factor for a better response to eradication ther-

https://doi.org/10.1016/j.ajg.2019.05.006
1687-1979/Ó 2019 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
92 A. Capannolo et al. / Arab Journal of Gastroenterology 20 (2019) 91–94

apy compared to those without duodenitis [19–21]. Another inter-
esting finding in this regard is that dyspeptic patients presenting
early satiety present duodenal eosinophilia [15,16,22,23].
In a previous prospective study conducted in a small cohort of
patients, we observed that duodenal microscopic inflammation,
in particular duodenal lymphocytosis, is significantly associated
with H. pylori infection in patients with FD, but not in asymp-
tomatic control subjects (p = 0,001; OR: 12; 95% CI: 2.422–
59.454) [24].
The present study aimed at confirming in a larger cohort of
patients, the supposed role of antro-duodenal low-grade inflam-
mation in FD, evaluating the frequency of duodenal lymphocytosis,
H. pylori infection and their association in a group of patients with
FD compared to an asymptomatic control group.
Patients and methods
Study design
This cross-sectional, observational study has been conducted
screening all the patients who underwent duodenal biopsies dur-
ing upper endoscopy, in the period between October 2011 and
March 2014, in the Gastroenterology Unit of the University of
L’Aquila. All the patients without endoscopic lesions and with
biopsies taken from both stomach and duodenum were studied.
Clinical and endoscopic data were retrieved from patients’ medical
records.
Study group
Patients who fulfilled Rome III criteria for the diagnosis of FD
were selected and sub-classified as PDS, EPS or PDS + EPS.
Control group
Randomly selected subjects who were symptom-free in the
population subjected to endoscopy. In particular, they did not have
FD, gastro-oesophageal reflux symptoms or IBS.
Patients with the diagnosis of coeliac disease, positive screening
for IgA tissue transglutaminase (tTG), organic diseases, irritable
bowel syndrome (IBS), gastro-oesophageal reflux symptoms and
pregnancy were excluded.
The study was performed in accordance with the declaration of
Helsinki [25] and all the study subgects gave their written
informed consent prior to their inclusion in the study.
variables were H. pylori infection and the following: age, gender,
drugs, FD subgroups (FD PDS, EPS) and single symptoms.
Duodenal lymphocytosis was dichotomized according to its
presence or absence. H. pylori infection was dichotomized accord-
ing to its presence or absence. Values of P < 0.05 were considered
significant.
Statistical analysis was performed using the SAS statistical soft-
ware (version 9.2, 2002–2008; SAS Institute, Inc., Cary, NC).
Results
The study design is schematically outlined in Fig. 1.
Over the 30 month-period, 303 patients were screened; of these
87 were not enrolled due to violation of inclusion criteria or appli-
cability of exclusion criteria. Thus, 216 patients were analysed: 161
as FD group and 55 as asymptomatic controls.
The mean age was 41.11 years and 161 were females. The two
groups characteristics are summarized in Table 1.
As far as FD patients concerns, 81 were sub-classified as EPS
(50.31%), 51 as PDS (31.67%) and 29 as EPS + PDS (18.01%).
The most commonly referred symptom was epigastric pain - in
87 patients (54.03%), followed by bloating – in 66 patients
(40.99%), epigastric burning – in 47 patients (29.19%), early sati-
ety/postprandial fullness – in 15 patients (9.31%) and nausea – in
5 patients (3.10%).
Histology
Cases and controls (Fig. 2, Table 2)
Fig. 2 shows histological findings in the FD group and the con-
trol group, while Table 2 refers to FD sub-groups.
Duodenal lymphocytosis was equally present (p = 0.99) in FD
patients (25.47%) and controls (25.45%). No statistical differences
were found among EPS, PDS and EPS + PDS sub-groups (19.75%,
29.41% and 34.48% respectively).

Endoscopy and biopsies

Upper endoscopy was performed by expert gastroenterologists.

During endoscopy, 4 biopsy specimens from the second duodenal
part and 3 biopsies from the gastric antrum were obtained. All
biopsies were fixed in formalin and stained with haematoxylin
and eosin. Duodenal biopsy samples were placed on filter paper
and evaluated with immunohistochemical procedures to count
intraepithelial lymphocytes (IELs) CD8+. Duodenal lymphocytosis
was defined as 25 or more IELs per 100 enterocytes, in the presence
of normal villous architecture [26–28]. Gastric biopsies were eval- Fig. 1. Flow chart illustrating the study design. EGDS: OesophagoGastroDuo-
uated for the presence of H. pylori infection and the grade of denoscopy; CD: coeliac disease.
inflammation.

Statistical analysis
Table 1
Groups were compared by non parametric Chi Square or Fish- Pre-study characteristics of the study population.
er’s exact tests as appropriate. Subsequently, to assess the associa-
FD patients Controls
tion of duodenal lymphocytosis with H. pylori infection, a logistic
regression model was employed in which the dependent variable Gender (male/female) 35/126 20/35
Mean Age (years) 39,97 44,43
was the presence of duodenal lymphocytosis and the independent
 A. Capannolo et al. / Arab Journal of Gastroenterology 20 (2019) 91–94
Fig. 2. Histological findings in the FD group and the control group.
H. pylori infection prevalence was not different (p = 0.78)
between patients and controls (26.71%, 23.64% respectively) as
well as in EPS, PDS and EPS + PDS sub-groups of patients (35.80%,
39.21% and 13.79 respectively).
The simultaneous presence of duodenal lymphocytosis and H.
pylori infection was significantly more prevalent (p = 0.047) in
patients respect to controls (10.55% and 1.81% respectively), whilst
no differences were found among sub-groups (12.34%, 19.60% and
13.79% in EPS, PDS and EPS + PDS respectively).
FD symptoms (Table 3)
Duodenal lymphocytosis was significantly (p = 0.0082) associ-
ated with bloating (36.36%) whilst no difference was found in the
prevalence of epigastric pain (21.83%), epigastric burning
(31.91%), early satiety/postprandial fullness (26.66%) and nausea
(none).
No significant prevalence of H. pylori infection was found
among patients with epigastric pain (32.18%), bloating (28.78%),
epigastric burning (17.02%), early satiety/postprandial fullness
(20%) and nausea (40%).
Duodenal lymphocytosis and H. pylori infection were not statis-
tically associated to a single symptom such as epigastric pain
(9.19%), bloating (15.15%), epigastric burning (8.51%), early sati-
ety/postprandial fullness (13.33%) or nausea (none).
Discussion
Results of the present investigation show that, in our cohort of
dyspeptic patients, duodenal lymphocytosis is significantly associ-
Table 2
Distribution of hystological findings in FD subgroups.
Duodenal lymphocytosis
H. pylori
Duodenal lymphocytosis + H. pylori
Table 3
Hystological findings and symptoms.
Epigastric pain
N (%)
Duodenal lymphocytosis 19 (21.83)
H. pylori 28 (32.18)
Duodenal lymphocytosis + H. pylori 8 (9.19)
93
ated with bloating (p = 0.0082) and the simultaneous presence of
duodenal lymphocytosis and H. pylori infection is significantly
more prevalent respect to controls.
Bloating is an unspecific and frequent complaint reported by
76% of patients with functional gastrointestinal disorders associ-
ated with both lower and upper gastrointestinal symptoms [29].
Despite its clinical, social and economic relevance, the pathophys-
iology of bloating and abdominal distension is complicated and
incompletely understood, and no treatment is reported as univer-
sally effective [30].
The role of low-grade inflammation of the duodenum has
received growing attention in the last years in the attempt to bet-
ter understand FD pathogenesis.
An increased duodenal IELs count with normal villous architec-
ture has been shown to be a common unspecific finding with an
increasing frequency over time [31]. It has generally been associ-
ated with H. pylori gastritis, gluten sensitivity or other food hyper-
sensitivity, viral enteritis, intestinal infections, bacterial
overgrowth, drugs (NSAID, PPI), immunological disorders, obesity
and microscopic colitis. Sometime, however, it is idiopathic
[26,32] and its role is still to be elucidated.
A recent study demonstrated that a mild to moderate degree of
duodenal inflammation was an invariable feature noted in a group
of patients with FD, with a raised duodenal IEL noted in 72% of the
cases [33].
Another result of the present investigation is that 94% of the
subjects with the contemporaneous presence of duodenal lympho-
cytosis and H. pylori infection suffer from dyspepsia. Similar
results have been described by Gargala and colleagues: a higher
duodenal IEL count in dyspeptic H. pylori positive patients respect
to healthy controls, but not in H. pylori negative dyspeptic patients
[14].
Far to give a definitive explanation, it seems that symptoms are
present when inflammation involves the entire antro-duodenal
region. Gastric antrum, pyloric sphincter and duodenum can be
considered a unique anatomo-functional entity for the tight rela-
tionship that they have in regulating gastric emptying, alkalinisa-
tion of duodenal bulb or preventing duodeno-gastric reflux, all
phenomena whose alterations can lead to dyspeptic symptoms;
besides motor or sensory dysfunctions previously demonstrated,
duodenal mucosal immune changes could exist in FD.
A limit of our study is the inclusion of dyspeptic patients having
H. pylori gastritis in the study population, as the study was
designed prior to the Kyoto consensus which definitively distin-
guished H. pylori associated dyspepsia from FD, for those patients
with a long-lasting response to eradication therapy [34], and
because Rome III classification does not require ruling out of
EPS 81 PDS 51 EPS + PDS 29
N (%) N (%) N (%)
16 (19.75%) 15 (29.41%) 10 (34.48%)
29 (35.80%) 20 (39.21%) 4 (13.79%)
10 (12.34%) 10 (19.60%) 4 (13.79%)
Bloating Burning Early satiety Nausea
N (%) N (%) N (%) N (%)
24 (36.36) 15 (31.91) 4 (28.57) 0
19 (28.78) 8 (17.02) 3 (21.42) 2 (40)
10 (15.15) 4 (8.51) 2 (14.28) 0
94 A. Capannolo et al. / Arab Journal of Gastroenterology 20 (2019) 91–94
H. pylori infection for diagnosing FD. According to our observation
however, duodenal lymphocytosis is associated with bloating, only
in the absence of H. pylori infection, excluding symptoms to be
derived from H. pylori gastritis.
Our investigation is lacking in eosinophils evaluation. This
study in fact, originates to confirm a previously observed associa-
tion between duodenal lymphocytosis and H. pylori infection in
dyspeptic patients. Surely, given literature data, eosinophil count
should be take into account in the work up for functional
dyspepsia.
Further prospective, case-control studies are needed to confirm
data and to better understand a possible underlying pathophysio-
logic relationship.
In conclusion, the present investigation shows that in dyspeptic
patients, bloating is associated with duodenal lymphocytosis and
that dyspeptic symptoms seem to be related to a low-grade inflam-
mation of the functional unit represented by antro-duodenal
region, whose motor and secretory un-coordination is responsible
of FD.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
None.
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