IJC

International Journal of Cancer

Incidence and risk factors for the development of chronic

atrophic gastritis: five year follow-up of a population-based
cohort study
Mariam Abdullahi Adamu, Melanie Nicole Weck, Dietrich Rothenbacher and Hermann Brenner
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany

Chronic atrophic gastritis (CAG) is a well-established precursor of intestinal gastric cancer. However, data on incidence of CAG
are rare, especially from population-based studies. The aim of this analysis was to estimate the incidence of CAG in a large
population-based study among older adults from Germany and to identify major risk factors associated with its development.
In the baseline and 5-year follow-up examinations of the ESTHER study, serological measurements of pepsinogen (PG) I and II
and Helicobacter pylori antibodies were performed in 5,229 women and men, aged 50–74 years at baseline. Information on
additional potential risk factors was obtained by questionnaire. CAG was defined by PGI < 70 ng/mL and PGI/PGII < 3. In
total, there were 58 (1.1%) incident CAG cases. CAG incidence increased with increasing age from 0.5% in age group 50–54
years to 2.1% in age group 70–74 years. Seropositivity with H. pylori was strongly associated with CAG incidence, with
adjusted odds ratios of 5.0 [95% confidence interval (CI): 1.6–15.8] and 11.3 (95% CI: 4.2–30.0) for participants with
cytotoxin associated gene A (cagA) negative and cagA positive H. pylori infection at both baseline and follow-up compared to
those without H. pylori infection, respectively. Gender, education, smoking, alcohol consumption and family history of gastric
cancer were not significantly associated with CAG incidence. Incidence of CAG is rather low in the German population. Older
age and infection with H. pylori are key risk factors for the development of CAG.

With 700,000 deaths per year worldwide, gastric cancer
remains the second leading cause of cancer deaths worldwide,
despite a major decline in incidence and mortality in the past
decades.1 Chronic atrophic gastritis (CAG) is an essential
precursor lesion in the development of intestinal type of gas-
tric cancer.2,3 It is widely accepted that gastric carcinogenesis
is a continuous process leading via glandular atrophy and
metaplasia/dysplasia to adenocarcinoma, and it is assumed
that most gastric cancer cases have had preceding atrophy.4,5
Epidemiology
mostly included selected study populations, the majority of
which consisted of patients with a variety of gastric disor-
ders.7–14 In the population-based gastroscopy studies by Cor-
rea et al.15 and Vorobjova et al.16 conducted in high risk
populations of Columbia and Estonia, incidence of CAG was
reported to be 7.1% per year (in the gastric corpus and
antrum simultaneously) and 1.9% per year (in the gastric
corpus), respectively. In two other population-based studies
from Japan,17,18 in which different pepsinogen-based defini-

However, very little is known about incidence rates of
CAG as most studies on this lesion have been cross-sec-
tional.6 The few existing longitudinal studies reported inci-
dences ranging from 0 to 11% per year. However, they
Key words: incidence, chronic atrophic gastritis, gastric atrophy,
pepsinogen, Helicobacter pylori
Grant sponsors: Ministry of Research, Science and the Arts Baden-
Württemberg, German Federal Ministry of Family, Senior Citizens,
Women and Youth, Grant sponsor: German Federal Ministry of
Health and Education; Grant number: 01KH0404
DOI: 10.1002/ijc.25476
History: Received 14 Apr 2010; Accepted 14 May 2010; Online 25
May 2010
Correspondence to: Hermann Brenner, Division of Clinical
Epidemiology and Aging Research, German Cancer Research Center,
Bergheimer Str. 20, D-69115 Heidelberg, Germany, Tel.:
+49-6221-548140, Fax: þ49-6221-548142, E-mail: h.brenner@
dkfz-heidelberg.de
tions were used to define CAG, annual CAG incidences were
reported to be 2.7% and 1.3%, respectively.
Infection with Helicobacter pylori is known to be a major
risk factor for the development of CAG9,19; however, nearly
all studies on this association have been cross-sectional19 and
evidence from longitudinal settings is sparse.13,17,20,21 Simi-
larly, longitudinal data on other potential risk factors associ-
ated with the incidence of CAG are very sparse.
The aim of this prospective population-based cohort study
from Germany was to estimate the incidence of CAG among
older adults during 5-year follow-up and to identify potential
risk factors associated with CAG development.
Material and Methods
Study population
The ESTHER study is a large prospective population-based
cohort study carried out in Saarland, a federal state in the
south-west of Germany. The study was established to investi-
gate potential avenues of prevention and early detection of

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Adamu et al.
Figure 1. Flowchart of the study population. Abbreviations: CAG, chronic atrophic gastritis; PG, pepsinogen.
chronic diseases in the elderly. Details of the study design
have been reported elsewhere.22–26 Briefly, participants were
recruited from 2000 to 2002 by their general practitioners
during a general health check-up. The baseline study popula-
tion included 9,953 men and women, aged between 50 and
74 years. Follow-up examinations after 2 and 5 years were
carried out in 2002–2004 and 2005–2007, respectively. The
study was approved by the ethics committees of the medical
faculty of the University of Heidelberg and of the medical
board of the state of Saarland. Written informed consent was
obtained from each participant.
Data collection
Questionnaires. All participants completed a comprehensive
standardized questionnaire at baseline, providing information
on socio-demographic characteristics, medical history, health
status, family history and lifestyle factors. At 2-year follow-up
and 5-year follow-up, self-administered standardized ques-
tionnaires were applied to assess current health and lifestyle,
to identify changes through the years, and to screen for inci-
dence of major diseases. Self-reported major diseases were
validated by physicians’ reports, and dates and causes of
death of deceased participants were determined through pop-
ulation registries and public health offices.
Serological examinations. Serum samples were obtained
from the study participants at baseline and 5-year follow-up,
mailed to a central laboratory and stored at
80 C. At base-
line, blood samples were drawn from all participants by their
general practitioner during recruitment. At 5-year follow-up,
participants were sent a blood collection kit along with the
questionnaire and were asked to have a blood sample drawn
at their next general practitioner visit. However, participation
without blood sampling was also possible. Serum concentra-
tions of pepsinogen (PG) I and II were determined at base-
Int. J. Cancer: 128, 1652–1658 (2011) V
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1653
line and 5-year follow-up by an enzyme-linked immunosor-
bent assay (ELISA) [Biohit, Helsinki, Finland]. Additionally,
all baseline and follow-up samples were analyzed by ELISA
for the presence of immunoglobulin G antibodies both
against H. pylori in general and specific to the cytotoxin asso-
ciated gene A (cagA) of H. pylori [H. pylori Screening ELISA
and H. pylori p120 (cagA) ELISA, ravo Diagnostika, Freiburg,
Germany]. Classification of infection status followed the
manufacturer’s instructions; borderline results were treated as
negative. Validation of the H. pylori Screening ELISA test
was performed by comparing the H. pylori immunoglobulin
G serostatus against the results of the C13-urea breath test
(for which accuracy similar to gastroscopy-based gold stand-
ard has been shown) in 205 adult blood donors aged 40 to
68 years. Sensitivity and specificity of the serological test
Epidemiology
were 96% [95% confidence interval (CI): 92–100%] and 74%
(95% CI: 66–82%), respectively. All laboratory analyses were
carried out in a blinded fashion.
Statistical analyses. Statistical analyses were carried out by the
SAS statistical analysis software, release 9.2. Correlations
between PGI and PGII levels, and the PGI/PGII ratio were
assessed by Spearman’s correlation coefficients. Defined afore,
CAG was defined as PGI < 70 ng/mL and PGI/PGII < 3, as
this definition has been used most frequently in previous popu-
lation-based studies.6 Incidence of CAG was estimated for the
total population and according to potential risk factors. Uncon-
ditional logistic regression analyses, with adjustment for age
and sex, and additional adjustment for multiple covariates were
used to estimate odds ratios (ORs) and their 95% CIs. The fol-
lowing potential risk factors were included in the fully adjusted
model: age, sex, education, smoking, alcohol consumption, fam-
ily history of gastric cancer and cagA negative or positive H.
pylori infection. Baseline smoking status was classified into
three groups (current, former and never smokers). Alcohol
 1654 Incidence and risk factors for CAG

consumption at baseline was assessed by the average amount of were very similar as in all subjects with available PG levels at
weekly alcohol consumption within the previous 12 months. In baseline who were free of CAG and gastric cancer at baseline
the first part of the analyses, H. pylori serostatus at baseline and did not die during follow-up (N ¼ 8,463, 55.8% women,
only was included in the models. However, as association of mean age: 62 years).
serostatus with incidence of CAG may be attenuated by mea- Table 2 depicts correlations between PG levels at baseline
surement error or loss of infection during follow-up (e.g., and follow-up. Strong positive correlations exist between PGI
through eradication), additional analyses were carried out after and PGII both at baseline and follow-up and also when com-
exclusion of participants with inconsistent H. pylori serostatus paring baseline and follow-up data of the respective PG levels.
at baseline and follow-up. Overall, 58 incident cases of CAG (1.1%) meeting the PG-
based diagnostic criterion (PGI < 70 ng/mL and PGI/PGII <
Results 3) at follow-up were identified, which corresponds to an annual
During the 5-year follow-up, 499 (5.0%) of the 9,953 study incidence of 0.2%. Table 3 gives an overview of the incidence
participants died. From the remaining women and men, at 5-year follow-up according to various potential risk factors.
8,274 (87.5%) participated at 5-year follow-up. Blood samples Although the absolute incidence was slightly lower in females,
for PG measurements were available from 9,426 participants there was no significant association with sex. Five year inci-
at baseline and from 5,738 participants at 5-year follow-up. dence continuously increased with increasing age ranging from
All 5,229 subjects for whom PG data was available at baseline 0.5% in the youngest age group to 2.1% in the oldest age group
and follow-up, and who were free of CAG at baseline and (p-value for trend ¼ 0.01). Compared to the youngest age
who were not diagnosed with gastric cancer at either baseline group, positive significant associations were seen for the two
or follow-up were included in the analyses (Fig. 1). oldest age groups with ORs of 3.3 (95% CI: 1.1–9.8) and 4.6
As Table 1 shows, the study population included 2,849 (95% CI: 1.5–13.8) in the age- and sex-adjusted analyses. Edu-
women (54.5%) and 2,380 (45.5%) men, with a mean age of cation, smoking, alcohol consumption and family history of
62 years at baseline. Proportions of women and mean age gastric cancer did not show statistically significant associations
with the incidence of CAG. Seropositivity for H. pylori was pos-
Table 1. Characteristics of the study population itively associated with the incidence of CAG. Compared to sub-
Males, N (%) Females, N (%) Total, N (%)
jects who were H. pylori negative at baseline, infection with the
bacterium at baseline yielded ORs of 3.4 (95% CI: 1.6–7.5) for
Total 2380 (100) 2849 (100) 5229 (100)
infection with cagA negative H. pylori strains and 5.9 (95% CI:
Age at baseline (years) 2.9–12.0) for cagA positive H. pylori strains. Multivariable
50–54 377 (15.8) 478 (16.8) 855 (16.3) adjustment for all variables in the Table led to similar ORs as
55–59 387 (16.3) 518 (18.2) 905 (17.3) adjustment for age and sex only.
60–64 709 (29.8) 816 (28.6) 1525 (29.2) Overall, consistent findings for H. pylori and cagA sero-
65–69 572 (24.0) 662 (23.2) 1234 (23.6)
logical status at baseline and follow-up were obtained for
4,208 participants. After restriction of the analyses to these
70–74 335 (14.1) 375 (13.2) 710 (13.6)
participants, much stronger associations of H. pylori infec-
Mean 62.2 61.9 62.0
Epidemiology

tion with the incidence of CAG emerged. Adjusted ORs

Table 2. Correlations between PGI, PGII and PGI/PGII ratio at baseline and follow-up [Spearman’s correlation coefficient (p-value)]
Baseline 5-year follow-up
PGI PGII PGI/PGII PGI PGII PGI/PGII
Baseline PGI 0.71 0.13 0.55 0.47
0.13
(<0.0001) (<0.0001) (<0.0001) (<0.0001) (<0.0001)
PGII
0.53 0.36 0.59
0.49
(<0.0001) (<0.0001) (<0.0001) (<0.0001)
PGI/PGII 0.11
0.31 0.58
(<0.0001) (<0.0001) (<0.0001)
5-year follow-up PGI 0.71
0.05
(<0.0001) (0.0002)
PGII
0.69
(<0.0001)
PGI/PGII

Abbreviation: PG, pepsinogen.

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Adamu et al. 1655

Table 3. 5-year incidence of chronic atrophic gastritis (PGI < 70 ng/mL and PGI/PGII < 3) according to potential risk factors
N1 Incident cases (%) OR2 95% CI OR3 95% CI
Total population 5,229 58 (1.1)
Sex
Male 2,380 30 (1.3) ref ref
Female 2,849 28 (1.0) 0.79 0.47–1.33 0.72 0.37–1.41
Age (years)
50–54 855 4 (0.5) ref ref
55–59 905 7 (0.8) 1.66 0.49–5.70 2.33 0.60–9.10
60–64 1,525 13 (0.9) 1.82 0.59–5.60 2.10 0.58–7.62
65–69 1,234 19 (1.5) 3.31 1.12–9.77 2.93 0.82–10.48
70–74 710 15 (2.1) 4.56 1.51–13.80 5.21 1.45–18.69
Education (years)
9 3,762 40 (1.1) ref ref
10 to 11 770 7 (0.9) 0.90 0.40–2.02 1.17 0.51–2.70
12 586 7 (1.2) 1.06 0.47–2.41 1.46 0.63–3.41
Smoking
Never smoker 2,646 29 (1.1) ref ref
Former smoker 1,761 18 (1.0) 0.88 0.46–1.68 1.09 0.55–2.15
Current smoker 630 7 (1.1) 1.24 0.53–2.91 1.32 0.52–3.35
Alcohol
No alcohol 1,495 19 (1.3) ref ref
<60 g/week 1,450 15 (1.0) 0.79 0.40–1.57 0.91 0.43–1.95
60–140 g/week 1,268 16 (1.3) 0.84 0.42–1.69 1.08 0.51–2.28
>140 g/week 699 4 (0.6) 0.37 0.12–1.13 0.34 0.09–1.24
Family history of gastric cancer
No 4,915 54 (1.1) ref ref
Yes 314 4 (1.3) 1.15 0.41–3.21 1.15 0.35–3.77
Helicobacter pylori infection at baseline
H. pylori
2,606 10 (0.4) ref

Epidemiology
H. pylori þ/cagA
1,226 17 (1.4) 3.40 1.55–7.46 3.03 1.28–7.14
H. pylori þ/cagA þ 1,307 31 (2.4) 5.87 2.86–12.04 5.55 2.57–11.98
1
Numbers do not always add up to the total due to missing values. 2adjusted for age and sex. 3adjusted for all other variables in the Table.
Abbreviations: CagA, cytotoxin associated gene A; CI, confidence interval; OR, odds ratio; PG, pepsinogen.

(95% CI) were 5.0 (1.6–15.8) for cagA negative infection
and 11.3 (4.2–30.0) for cagA positive H. pylori infection
(Table 4).
Discussion
In this large population-based cohort study among older
adults in Germany, incidence of CAG was found to be rather
low. Very strong, positive associations were seen with age
and H. pylori infection, in particular infection with cagA pos-
itive H. pylori strains. The highest ORs were observed for
participants who maintained a cagA positive H. pylori infec-
tion during the study period. Gender, education, smoking,
alcohol consumption and family history of gastric cancer did
not show any significant associations with the incidence of
CAG; however, the small number of affected cases may have
limited the power and has to be considered.
Few longitudinal studies have assessed incidence of CAG
and most of these studies were conducted among special
high risk populations (with varying age at baseline, ranging
from 18 to 84 years),7,12–14,27,28 yielding estimates of annual
incidence up to 11%. The results from this population-based
study suggest that incidence of CAG might be substantially
lower in the general population of a highly developed West-
ern country even at advanced ages.
The positive associations of CAG with H. pylori infection
and age are consistent with previous findings,15,17 which were
mostly based on cross-sectional studies.19 Overall, the observed
associations of H. pylori infection with CAG were even

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 1656 Incidence and risk factors for CAG

Table 4. Incidence of chronic atrophic gastritis (PGI < 70 ng/mL and PGI/PGII < 3) according to serostatus of Helicobacter pylori among
participants with consistent serostatus at baseline and follow-up
N Incident cases (%) OR1 95% CI OR2 95% CI
Total 4,208 43 (1.0)
Helicobacter pylori infection at baseline and follow-up
H. pylori
2,494 6 (0.2) ref ref
H. pylori þ and cagA
697 10 (1.4) 5.6 2.0–15.6 5.0 1.6–15.8
H. pylori þ and cagA þ 1,017 27 (2.7) 10.8 4.4–26.2 11.3 4.2–30.0
1
Adjusted for age and sex. 2adjusted for age, sex, education, smoking, alcohol consumption and family history of gastric cancer. Abbreviations:
CagA, cytotoxin associated gene A; CI, confidence interval; OR, odds ratio; PG, pepsinogen.

stronger than reported in previous studies. One possible reason
is related to the definition of CAG. In our study, CAG was
defined as a combination of PGI < 70 ng/mL and PGI/PGII <
3. As previously shown, association of H. pylori infection with
CAG have been much weaker or even absent in studies using
an alternative definition, based on PGI alone (PGI < 25 ng/
mL).19,24 When this latter definition was used in our study in
additional sensitivity analyses, the strength of the H. pylori-
CAG association was substantially reduced, and age was no
longer a significant predictor of CAG (data not shown).
It is well known that serological measurement of H. pylori
infection is less than perfect29 and that misclassification of the
infection may lead to underestimation of the association with pos-
sible disease outcomes including CAG. To minimize potential
underestimation of the association by misclassification of H. pylori
infection, we carried out additional analyses with consistent meas-
urements of H. pylori infection only. Apart from reduction of pos-
sible misclassification, the restriction could also have led to exclu-
sion of subjects with recurrent infection after prior treatment or of
subjects in whom H. pylori infection was eradicated after baseline.
We, therefore, believe that the much stronger association seen af-
ter the restriction provides a more valid estimate of the impact of
H. pylori infection on CAG incidence. Support for a causal, strong
Epidemiology
analysis which was though restricted to the category relatively
with high amounts of alcohol and was not statistically signifi-
cant, given the small numbers of incident cases.
In the interpretation of our study, a number of limitations
have to be kept in mind. CAG was diagnosed by pepsinogen in
our study and its presence was not confirmed by histology.
Although the histological method is considered the gold stand-
ard for clinical diagnoses of CAG, interobserver variability for
diagnoses of gastric atrophy on biopsy specimens has been
shown to be high,36,37 and sampling error exists,38 especially
when multifocal CAG is present.39 In contrast, the measure-
ment of pepsinogen levels provides a standardized, integrative
measurement of the status of the entire gastric mucosa that
allows to include a very large number of the population of in-
terest. Nevertheless, the difficulty of definite diagnosis of atro-
phy is a limitation of all research and publications on the epide-
miology of CAG, as specification of the best serological
definition of CAG is difficult to accomplish.24
The study participants were recruited during a voluntary
health check-up and the study population is not a true ran-
dom sample from the underlying general population. How-
ever, participants have been shown to be similar to the Ger-
man population with respect to major sociodemographic and

relationship between H. pylori infection and CAG also comes
from H. pylori eradication studies, showing significant reduction
of gastric atrophy after H. pylori eradication.30
The role of smoking and alcohol consumption in the devel-
opment of CAG is controversial.21,31,32 Two follow-up studies
found a modest to relatively high positive association of smok-
ing with development of CAG,21,33 which was not the case in
our study and in most previously reported studies.17,32,34 Results
regarding the association of alcohol consumption with CAG de-
velopment have also been inconsistent.17,25,34,35 In a cross-sec-
tional analyses of our baseline data, moderate alcohol consump-
tion was found to be associated with a reduced risk for CAG.25
A tentative inverse association of alcohol consumption with
CAG development was also seen in the current longitudinal
socioeconomic factors.22 There was some loss to follow-up,
and blood samples were not obtained from all participating
at follow-up, but those subjects for whom blood samples
were available did not differ considerably from the baseline
population with respect to major sociodemographic factors.
In conclusion, in this large longitudinal population-based
study among older adults in Germany, we observed a rather
low incidence of CAG. H. pylori infection, in particular infec-
tion with cagA positive strains, was strongly related to the
development of CAG. Further research should address the
possible relevance of other putative H. pylori virulence fac-
tors, the interaction of the infection with other factors, such
as diet, and the potential of preventing CAG development or
progression by H. pylori eradication.

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