1. No category

Pediatrics International (2007) 49, 220–225
doi: 10.1111/j.1442-200X.2007.02329.x
Original Article
Long-term aspects of nodular gastritis in children
MUSTAFA AKCAM, REHA ARTAN, TEKINALP GELEN,1 AYGEN YILMAZ, ERDAL EREN,3
VEDAT UYGUN2 AND HIKMET CIG2
Medical School, Departments of 1Pathology and 2Pediatrics, Akdeniz University, Antalya, and 3Medical
School, Department of Pediatrics, Suleyman Demirel University, Isparta, Turkey
Abstract
Background: Close association of nodular gastritis and Helicobacter pylori infection has been initially proved
by various studies. There have been some studies reporting microscopic and histologic recovery in a short time
after eradication therapy. But there is not enough data about the long-term course of this condition. The aim of
this study is to document current clinical conditions, presence of H. pylori and results of endoscopic and histologic examination, after a long-term period, in children with endoscopically diagnosed antral nodularity.
Methods: A total of 35 patients diagnosed as nodular antral gastritis by upper gastrointestinal endoscopy during a 2 year period, were invited for re-evaluation and re-endoscopy after 3 years. Histopathologically, H. pylori
detected ones had been treated with standard triple eradication therapy. In total, 27 patients were accepted for
enrollment in the study. Repeated endoscopy could be performed in all 27 patients.
Results: The persistence of antral nodularity was detected in 18 of 27 patients. Decrease in symptoms, absence
of symptoms and presence of H. pylori infection were detected in 6, 8 and 16 (89%) of them, respectively.
There was no statistical significance between the first and last endoscopic biopsies when activity, atrophy, intestinal metaplasia and presence of follicles were regarded. Malt lymphoma could not be detected in any of the
patients.
Conclusion: There is a strong association between nodular gastritis and H. pylori. Presence of antral nodularity in the long-term period may be related to H. pylori re-infection. New therapeutic approaches are required
for treatment and management of the patients diagnosed as nodular gastritis and living in areas endemic for
H. pylori infection.
Key words
childhood, course, Helicobacter pylori, nodular gastritis.
Nodular gastritis (NG) is usually characterized as presenting
with an endoscopic appearance that has been described as
‘goose flesh’.1 It is also characterized by intense inflammatory
cell infiltration consisting mainly of monocytes and by increased
numbers of lymphoid follicles with a germinal center, in gastric
mucosa.2
It has been known that common and universally distributed
Helicobacter pylori infection is the most frequent reason for
gastritis and peptic ulcer disease. This infection, predominantly
acquired in childhood, has been accepted as directly associat-
Correspondence: Mustafa Akcam, Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition,
Akdeniz University, Medical School, Çocuk Sağlığı ve Hastalıkları
AD, Antalya 07059, Turkey. Email: [email protected]
Received 11 October 2005; revised 1 December 2005; accepted
26 December 2005.
ed with gastric carcinoma and mucosa-associated lymphoid
tissue (MALT) lymphoma.3 The inflammation that H. pylori
causes in the gastric mucosa is not always observed macroscopically with endoscopy, but it is identified on the histologic
examination of gastric biopsies.4
A strong association between endoscopic detection of NG
and presence of H. pylori has been established in previous
studies.1,2,5–8 There are a few reports mentioning recovery of
this nodular appearance after eradication treatment.5,9 There
is no definite reason for antral nodularity, and we could not
recognize any study about long-term follow up and evaluation
of endoscopic and histologic changes after this time in the
literature.
In the present study, re-evaluation of clinical conditions,
presence of H. pylori and results of endoscopic and histologic
examination of children diagnosed as NG is aimed after a
mean 3 years follow up.
Nodular gastritis in children
221
Methods
Between January 2001 and December 2002, a total of 263
(143 female, 120 male) upper gastrointestinal endoscopies
were performed due to various indications. Antral nodularity
was detected endoscopically in 35 of them and 30/35 were
detected as infected with H. pylori. All H. pylori-positive patients received standard therapy (omeprazole or lansoprazole + amoxycillin + clarithromycin, for 14 days). All patients
were controlled both clinically and via stool antigen test
(Cromatest, Linear Chemicals, S.L. Barcelona, Spain) 6 weeks
after initiation of treatment. Six cases that were positive for
stool antigen received second line eradication therapy (ranitidine bismuth-citrate + tetracycline + amoxicillin 14 days, per
oral). At 4 weeks after termination of therapy, stool antigen
was still positive in three cases, although they were asymptomatic. A total of 35 patients diagnosed as NG were recalled
approximately 3 years after treatment for the purpose of clinical, endoscopical and histopathological evaluation. In total,
28 of them came to control, and only one refused endoscopy.
The data of the 27 eligible patients is shown in Figure 1. Four
of them were not infected with H. pylori at the first
evaluation.
Four of 35 patients with NG were diagnosed with celiac
disease during the first biopsy (pts 15, 16, 23, and 24). The
other two patients were followed up with the diagnosis of
chronic liver disease (chronic autoimmune hepatitis in pt. 17
and unknown origin in pt. 26). Mediastinal non-Hodgkin lymphoma developed during follow up of one patient (pt.2). All of
these patients were also among the group that was investigated
for a second time.
Endoscopy was performed by one of the authors. Endoscopy
was done using the Olympus EVIS CV-240 video endoscopes
(outer diameter = 9.5 mm; biopsy channel diameter = 2.8 mm)
with FB-24K-1 biopsy forceps. During endoscopy, all abnormalities seen are noted in a standardized report. The macroscopic aspect of the antrum is noted separately with special
attention for nodularity. The definition of endoscopic nodularity
was made when the mucosa had an irregular appearance resembling a cobblestone pavement (Fig. 2).
During endoscopy, two antral biopsies were taken in addition to biopsies obtained from esophagus, corpus and duodenum. One of the antral biopsy specimens were embedded in
the rapid urease test (CLO test duo; Ballard Medical Products,
Draper, UT, USA) which consist urea agar and pH indicator.
Other specimens were placed directly in 10% formalin without a paper filter, for histologic examination. One of the
authors, blinded to the patients’ endoscopic or clinical findings, examined the biopsies (stained with hematoxylin–eosin,
and Diff-Quick) for H. pylori and gastritis. H. pylori infection
was characterized by bacteria found with histologic examination, and density of organisms was rated low, moderate or
high. The diagnosis of gastritis was based on the histopatho-
Fig. 1 Election algorithm of the 27 patients.
logic findings of inflammation, activity, metaplasia, and atrophy. Each of these findings was scored as normal (−), mild (+),
moderate (++), or marked (+++) following the updated Sydney System and using visual analog scales.10
Symptoms and clinical findings of 27 patients, who could
be contacted 3 years after treatment, were recorded.
Patients were classified as H. pylori positive when histological investigation was positive, as the gold standard tool
for H. pylori infection. Exclusion criteria were a history of
gastric surgery; or the use of antacids, H2-receptor antagonists, proton pump inhibitors, antibiotics, steroids, or nonsteroidal anti-inflammatory drugs within 1 month before
endoscopy.
Statistical analysis was made with statistical software
program SPSS for Windows version 11.00 (SPSS, Chicago,
IL, USA), using the McNemar, ␹2 and Mann–Whitney
tests. The results were given as the mean ± SD. Statistical
significance was set at the 0.05 level. Informed parental
consent was obtained from all patients prior to entry into
the study.
222
M Akcam et al.
Fig. 2 Endoscopic nodular appearance of the antral mucosa.
Results
A total of 263 patients underwent upper gastrointestinal examination because of various indications; 107 of them (41%)
were H. pylori positive and 35 of them were diagnosed as (21
female, 14 male) NG. The prevalence of NG in children who
underwent endoscopy was 13% (35/263). NG showed a female
predominance (odds ratio = 1.3; 95% confidence interval,
0.63–2.69). H. pylori infection rate in NG patients was 86%
(30/35). CLO test were positive in 22 of 30 patients who were
infected with H.pylori, and one of five patients who weren’t
infected.
At initial endoscopic examination, mean age of 27 patients
who accepted control endoscopy was 11.2 ± 3.8 (range, 2–
16). H. pylori had been detected in 23 of them (85%) in the
first endoscopy. The median between the first and the last
endoscopy was 33 (24–46) months. According to last endoscopy, antral nodularity was found in 18 (66%) and H. pylori
were positive in 22 (81%) of the total 27 patients. All the
H. pylori-negative patients were confirmed by a stool antigen
test. H. pylori stool antigens were negative in five patients
with H. pylori histologically negative. H. pylori were positive in 16 of 18 (89%) and in 6 of 9 (67%) patients who had
antral nodularity or no nodularity, respectively. When
H. pylori density was scored from 0 to 3, mean densities were
1.43 ± 0.6 and 1 ± 0 in patients with nodularity and no nodularity, respectively (P = 0.08, Mann–Whitney test). Last
endoscopy of five H. pylori-negative patients revealed that
two patients (40%) had nodular appearance. NG was seen in
14 (61%) and H. pylori was positive in 19 (83%) of 23
patients who had H. pylori and received eradication therapy
after the first endoscopy. Duodenal ulcer was seen in one
patient without NG. Lymphoid follicles were detected in 11 of
27 (41%) patients during the first endoscopy, and were found
in six of 18 (33%) NG patients during second endoscopy.
There was no statistical significance between the first and last
endoscopic biopsies when histopathologic activity, atrophy,
intestinal metaplasia and presence of follicles were regarded
(P > 0.05 for all). In the last evaluation there was no atrophic
gastritis in three patients who had it initially. NG was detected
in two and was absent in four of six patients who had atrophy
in the second endoscopy. MALT lymphoma was detected in
none of the patients.
Although all 27 patients were symptomatic initially, only
15 of them (55%) were symptomatic in the last control. A total
of 13 of 23 patients (57%) who received eradication therapy
before, were symptomatic in the last control. Four of these 13
patients were symptomatic in spite of recovery of nodularity.
In total, 10 of 18 (55%) NG detected patients in the last control
were symptomatic whereas the remaining eight (45%) were
asymptomatic. The characteristics of the patients are given in
Table 1.
Discussion
The initial infection of H. pylori occurs more frequently during childhood, and endoscopic antral nodularity also occurs
more frequently in children than in adults.5 Antral nodularity
is the only sign with a high positive predictive value for the
presence of H. pylori infection.6,11 This finding may identify
patients in whom gastritis is more severe and associated with
marked bacterial colonization.5 Our study also establishes
the importance of endoscopic antral nodularity for suggesting H. pylori infection in children.
The almost 3:1 female predominance in NG was reported
in an adult study.1 We also found a slight female predominance
(3:2). A pattern of male predominance has been reported for
duodenal ulcer, whereas H. pylori infection shows no gender
predilection.12 This condition underlines the importance of
host factors for the formation of NG when H. pylori infection
is present.
Nodular gastritis in children
223
Table 1 The characteristics of the patients
Patient
No
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Age (year)/
gender
10/F
16/M§
12/F
10/F
15/F
6/M
15/F
15/F
14/F
13/F
10/F
14/F
15/F
10/F
2/M*
8/M*
5/F#
8/M
14/F
14/F
12/M
16/F
5/F*
7/M*
15/M
12/M#
10/F
Initial
symptoms
RAP,V
He, B,
He, RAP
RAP
N, He, B, V
V, RAP
RAP
RAP,V
RAP
RAP, V, Hea
RAP
He
RAP,V
RAP, Hea, He
An
RAP, He
RAP
Anemia
He, B, RAP
He, Hea
RAP
RAP
An, D,RAP, V
An
RAP
An, RAP
RAP, An,
Na, He, D
Initial
H. pylori
density
Type of
Gastritis
Symptom of
4–6 weeks after
eradication
therapy¶
Current
symptoms
−
−
−
−
+
+
++
++
+
+
+
+
++
+
+
+
+
+
++
++
++
++
++
+
+
++
+
C
C
C
C
CL‡
C
CL‡
CL‡
C
CL‡
CL
CL‡
C
CL‡
C
C
CL‡
CA
C
CL‡
CL‡
CA
CL‡
CL‡
CA
CL
C
NS
NS
Decrease
NS
Decrease
Decrease
NS
NS
NS
RAP
Decrease
NS
Decrease
NS
NS
NS
NS
NS
Decrease
Decrease
NS
NS
NS
NS
NS
NS
Decrease
RAP
NS
Decrease
NS
Decrease
Decrease
RAP
RAP
NS
RAP
Decrease
He
D
RAP, He
NS
NS
Decrease
NS
Decrease
NS
NS
Decrease
NS
NS
NS
NS
RAP, Ha
3 years later
Endoscopic
H.pylori
finding
density
H, E, DU
NG
NG
NG
H
NG
NG
NG
N
NG
DGR
H
NG
N
H,E
N
NG
N
NG
NG
NG
NG
NG
NG
NG
NG
NG
+
−
+
+
−
++
+
+
−
−
–
+
++
+
+
+
+
+
++
+
++
+
+
+++
+
++
+
Type of
Gastritis
C
N
CL
C
C
CL‡
CA
CA
CA
C
C
CA
CL‡
CA
CL‡
CA
CL‡
C
CL
C
CL‡
C
CL‡
CL‡
C
CL
C
§
Non Hodgkin lymphoma; *Celiac disease; #Chronic Liver Disease; ¶Only H.pylori-positive patients were treated; ‡ having lymphoid follicle;
–, normal; +, mild; ++, moderate; +++, marked.
An, anorexia with failure to thrive; B, belching; C, chronic; CA, chronic atrophic; CL, chronic lymphocytic; D, diarrhea; DGR, duodenogastric reflux; DU, duodenal ulcus; E, epigastric burning/pain; E, erosion; Ha, halitosis; He, heartburn; Hea, hematemesis; H, hyperemia; Na,
nausea; RAP, recurrent abdominal pain; V, vomiting; N, normal; NG, nodular gastritis; NS, no symptom.
NG appears to be a reversible sign of active H. pylori infection. After successful eradication of the bacterium, the antrum
becomes macroscopically normal.5–9 Sbeih et al. also reported
that the successful eradication for H. pylori led to regression of
NG in five cases.9 There is no specific symptom of H. pylori
infection except ulcer-related disease. Most studies on the
evolution of symptoms after eradication of infection have
failed to show any difference in symptoms between children in
whom the infection had or had not been eradicated.13,14 We also
found that the patients with H. pylori-positive NG became less
symptomatic following standard H. pylori eradication therapy,
in a short-term follow up. But in some of them, symptoms
relapsed over time and when they came to the last control, 13
of 23 (57%) patients were symptomatic. Four of them were
symptomatic even when recovery of nodular appearance was
detected. Among 17 patients with nodularity in the last control, 10 were symptomatic (59%) while seven were asymptomatic (41%).
Problems with antibiotic resistance in this age group are
increasing because of the frequent use of amoxycillin, clarithromycin and metronidazole for respiratory and gastrointestinal infections.15 We could not be informed about the
intake of antibiotics which could be related to the evolution
of NG.
The eradication success rate with the combination of metronidazole, clarithromycin and omeprazole was 53.2% in a
previous study, performed in Turkey in which resistance to
metronidazole was reported at 36.4%.16 The eradication rate
and clarithromycin resistance was reported as 75.5% and
18.2%, respectively.17
224
M Akcam et al.
It is reported that 70–80% of the adult population in Turkey
is infected with H. pylori,18 whereas this ratio was reported as
44.5% in children.19
Our aim was to answer what is the destiny of patients with
antral gastritis in the long-term follow up. But patients could be
followed at most 46 months in this study. During this time MALT
lymphoma did not develop in any of the patients but persistence
of nodularity in 61% of patients is a disturbing condition.
Persistence of nodular appearance in 61% and positivity of
H. pylori in 83% of patients after eradication treatment brings
to mind probability of relapse or re-infection. Although reinfection rates have been uncommon in adults, it varies from
2.4 to 20% for children.20–22 Multivariate analysis revealed that
only age at primary infection correlates with an increased risk
of re-infection.12 Additionally, early infection represents a
critical factor in the future development of complications later
in life.23 Success of eradication was confirmed only with stool
antigen test in our study. If we prove this test true, it is necessary to evaluate the high rate of positivity of H. pylori (81%)
during the second endoscopy as re-infection. We could not
explain such a high re-infection rate in these patients group.
There was no association between histologic findings of
chronic gastritis and persistence of NG. The relation between
NG and histopathologic atrophy must be evaluated by using a
larger patient population.
Diagnosis of celiac disease in four patients during first
endoscopy, presence of chronic liver disease in two patients, and
emergence of lymphoma during follow up in one patient are
interesting conditions which brings to mind a special immune
status in the host which may play a role for NG development.
Finally, a strong correlation between NG disease and
H. pylori infection was determined, as in previous studies.
After 3 years follow up, most H. pylori-negative patients (60%)
did not have nodular appearance, endoscopically. There seems
to be a positive relation between eradication and endoscopic
recovery. Only 19% of patients were bacteria free, 3 years after
successfull eradication treatment. Since NG patients have a
high re-infection rate, they have to be followed closely and
treated appropriately, by second and may be third line eradication treatments. It is very important and necessary to prevent
more serious problems probable in the future.
This study revealed that H.Pylori eradication treatment did
not guarantee normalization of NG findings in the long-term
follow up period. Therefore, new therapeutic policies for follow up and treatment of NG patients especially living in
endemic regions for H. pylori are necessary.
Acknowledgments
The authors wish to thank nurses Kezban Özkalay, Şehriban
Karakaya and Nehime Kara for their help and cooperation.
Also thanks go to Dr Hakan Gülkesen for help in statistical
analysis. This study was supported by Akdeniz University
Administration of Scientific Research Projects.
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