are there gender-specific differences in reflux disease and barrett's oesophagus?
TRANSCRIPT
Review
Keywords
Barrett’sesophagus
Gastroesophagealreflux disease
Intraepithelialneoplasia
Risk factor
Gender
Elisabeth Lippert, MDDepartment of InternalMedicine I, UniversityHospital Regensburg,Germany
Helmut Messmann, MDDepartment of InternalMedicine III, AcademicTeaching Facility, KlinikumAugsburg, Germany
Esther Endlicher, MDDepartment of InternalMedicine I, UniversityHospital Regensburg,Germany
E-mail:[email protected]
Online 1 February 2011
16 Vol. 8, No. 1, pp
. 1Are there gender-specificdifferences in refluxdisease and Barrett’soesophagus?
Elisabeth Lippert, Helmut Messmann and Esther EndlicherAbstract
Studies of the prevalence of gastroesophageal reflux disease (GERD) have reported that male gender is an
independent risk factor, especially for erosive reflux disease (ERD). Non-erosive GERD (NERD) is more
common in women. The prevalence and severity of reflux symptoms are found more often in older
women. In men, the peak is found between 50 and 70 years and decreases thereafter. The gender effect
may be due to differences in parietal cell mass between males and females but has not been investigated
extensively so far.
Barrett’s esophagus (BE) is a major complication of gastroesophageal reflux disease and is associated with
a 30–125 times increased risk of developing carcinoma. Different studies have found the male gender to
be predominantly associated with esophageal adenocarcinoma and BE. Additionally, there exists an age
shift between females and males of 20 years, which shows age-specific prevalence curves for males
between 20 and 59 years. The reasons for these gender-specific differences are largely unknown so far.
Male predominance for ERD as a precursor of BE may explain the greater male/female sex ratio for BE. It is
speculated that female sex hormones may play a protective role in the onset of BE.
Knowledge of gender-specific differences in reflux disease and BE may be helpful for improving
surveillance and screening strategies, although distinct recommendations are lacking so far. � 2010 WPMH
GmbH. Published by Elsevier Ireland Ltd.
Introduction
Gastroesophageal reflux disease (GERD)
encompasses different entities, namely non-
erosive reflux disease (NERD) without, and
erosive reflux disease (ERD) with, the endo-
scopic finding of inflamed mucosal changes
in the distal esophagus, Barrett’s esophagus
(BE), and extra-intestinal manifestations (e.g.
reflux associated hoarseness or asthma-like
symptoms). Clinically, NERD can not be differ-
entiated from ERD in terms of the intensity
and frequency of symptoms.
The diagnosis of BE includes the histological
detection of intestinal metaplasia in the eso-
phagus lining. Depending on the extent,
further classification can be made as long-seg-
6–20, March 2011
ment BE (�3 cm) and short-segment BE (<3 cm)
[1–3]. BE is a major complication of GERD.
Besides acid reflux, bile reflux also seems to
have an impact in the pathogenesis of BE [4,5].
Results from autopsies have shown a preva-
lence for BE of 0.4% in Western countries [6].
The incidence of GERD is given as 10–30%, of
which 10% present with BE [7,8]. However, it
has been shown that BE can also be found in
asymptomatic patients. In one study, Gerson at
al. documented a 25% prevalence for BE in
male asymptomatic veterans older than 50
years [9]. Other groups have also shown a pre-
valence of between 6–15% for BE in asympto-
matic individuals [10,11].
Patients with BE have a 30–125 fold increased
risk of developing esophageal adenocarcinoma
� 2010 WPMH GmbH. Published by Elsevier Ireland Ltd.
Review
[12–15]. Although the incidence of adenocarci-
noma has been rising in the past few years, the
risk of cancer in BE was overestimated in ear-
lier studies. Recent studies have shown that
the risk is around 0.5% per year [16]. The reason
for this discrepancy is mostly due to the meth-
ods used. It is thought that a selection of
severely sick and partly hospitalized patients
in earlier studies influenced the outcome
(referral centre bias).
The prognosis for adenocarcinoma is still
rather poor. The 5-year survival rate is around
11% [17]. The survival rate depends on the
tumor stage at diagnosis. Quite often, metasta-
sis has occurred before the onset of any symp-
toms. Lymph node metastasis is found in 5% of
intramucosal tumors and in 24% of submucosal
tumors [18]. Therefore, early diagnosis at a stage
with curative possibilities is the key for the
improvement of survival. New endoscopic tech-
niques, such as mucosa/submucosa resection,
or ablative therapy (photodynamic therapy or
radio frequency ablation) seem to be replacing
esophagectomy in patients in the early stages
and will become standard procedures in clinical
practice in the future. Major advantages of these
techniques compared to esophageal resection
are reduced morbidity and mortality [19].
So far it is not known why some patients
with recurrent ERD present with no signs of
BE. In other cases, patients have no symptoms
or inflamed mucosal lesions but develop exten-
sive BE. Genetic influences seem to trigger the
disease [20]. However, the exact mechanism for
the development of Barrett mucosa remains
unclear. Going back to the ‘‘stem cell’’ theory,
Barrett mucosa originates from pluripotent
stem cells in the esophagus. Depending on
the surrounding milieu, these cells can differ-
entiate into either squamous mucosa or
columnar epithelium [21,22].
Intraepithelial neoplasia is a major risk fac-
tor for the development of cancer in the eso-
phagus, this is similar to the adenoma–
carcinoma sequence in colorectal carcinoma.
The surveillance frequency is determined by
the grade of intraepithelial dysplasia [1]. With
respect to surveillance recommendations, pre-
dictive factors for developing cancer are impor-
tant. In this context, a distinct dominance of
male gender in patients with adenocarcinoma
of the esophagus [23,24] reveals the necessity
to further investigate and analyze the gender
specificity of reflux and BE.
GERD – gender specific differences
In general, a recent study by Flameling et al. [25]
reported that patients with chronic reflux
symptoms are significantly older, have a higher
body mass index and more often show pathol-
ogy, especially BE, when referred for upper
endoscopy (esophagitis in 50% and BE in
10%). Otherwise no gender-specific differences
were found.
Nevertheless, many studies have shown a
dominance of male gender in the prevalence
of GERD [26–32]. In the ProGERD study, it was
demonstrated that ERD occurred more often in
men than in women (58.8% vs. 54.4%) [26].
Another meta-analysis concluded that there
was a dominance of male gender in ERD (ratio
of males/females = 1.57/1), whereas in NERD the
ratio was 0.72/1 [27]. Additionally, studies by
Labenz et al. [26] and El-Serag et al. [28] have
confirmed that male gender was a risk factor for
the severity of ERD. Logistic regression analysis
revealed that being overweight, alcohol con-
sumption and smoking were risk factors for
the development of ERD. The study by Labenz
et al. [26] is, by far, one of the major prospective
multicenter studies (n = 5289). However, one
criticism is the fact that the analysis was not
correlated to the population. A selection bias
can, therefore, not be excluded.
Nilsson et al. [29] published a population-
based analysis in 2004: 58,596 residents in Nor-
way had been evaluated regarding the inci-
dence and severity of reflux symptoms. The
results were analyzed for age and gender asso-
ciation. The prevalence of heart burn and regur-
gitation was 31.4% overall, with 26% reporting
minimal symptoms and 5.4% severe symptoms.
A total of 11.6% had reflux symptoms at least
once per week. In women, the prevalence of
symptoms increased from 22.1% in the younger
agegroup (19–30 years) to 37.5% in those aged
70 years and above. In males, the prevalence
increased from 25.8% in the 19–30 years
agegroup to 36.0% in the 50–60 years agegroup.
After that, it decreased to 33.8% in those aged 70
years and older. The higher prevalence of severe
reflux symptoms in females compared to males
in the oldest agegroup could not be explained
by differences in body mass index (BMI), smok-
ing or alcohol consumption, dietetic factors or
physical activity. The decreasing prevalence of
reflux symptoms in the oldest group of men was
explained by the increased number of those
Vol. 8, No. 1, pp. 16–20, March 2011 17
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18 Vol. 8, No. 1, pp
with BE. It was assumed that the Barrett
mucosa has a higher resistance to acid com-
pared to normal mucosa.
In a cohort of 1,234 patients, Shimazu et al.
investigated, prospectively, the influence of
age, gender and function of the gastroesopha-
geal lining in endoscopically positive reflux
disease [30]. The overall prevalence of endosco-
pically positive GERD was 5.8% (72/1234). In
men, the prevalence was 7.5% (with no associa-
tion with age). In women, the prevalence was
significantly lower compared to men (4.3%),
but there was a significantly increased preva-
lence combined with severity at older ages.
With regard to functional abnormalities of
the gastroesophageal lining, there was a cor-
relation with diagnosis and severity of ERD.
Again, there was a correlation with age in
women, but not in men.
Another recent study investigated the influ-
ence of race, gender and social status on reflux
esophagitis and BE [31]. Over a 3-year period,
20,310 patients underwent endoscopy in two
specialized centres. As for the studies men-
tioned above, male gender was an independent
risk factor for the presence of reflux esophagi-
tis. A recent study included 410 patients with
GERD symptoms and 4,047 patients with no
symptoms. Like the studies already mentioned,
BE was more common in males. However, in
this study, BE, dysplasia and adenocarcinoma
were detected more often in asymptomatic
patients [32].
The reason for gender-specific differences
might be due to variation in the parietal cell
mass in men and women [33]. Animal experi-
ments in rats have shown that ovarectomy is
associated with a significant increase in par-
ietal cell mass and an augmentation of basal
acid secretion. These results lead to the hypoth-
esis that male and female sex hormones play
an important part in the development and
function of gastric parietal cells.
Barrett’s esophagus – gender-specific differences
Typically, BE is a disease of white men older
than 50 years [34,35]. Many studies have
shown a dominance of male gender mostly
reported as a male/female ratio of >2/1
[27,31,34,36,37]. One reason might be that
women present with less severe reflux esopha-
. 16–20, March 2011
gitis than men [26,27]. Female sex hormones
also seem to play a protective role in the
development of BE [33].
In a study of 796 patients with reflux symp-
toms, the risk factors for BE, and especially
those for gender-specific differences, were inves-
tigated [37]. The total prevalence of BE was 26%
(260/796), and the prevalence of BE in men was
significantly higher (32%, 146/462) compared to
that in women (18%, 63/334). Comparing
women and men with reflux symptoms, women
with symptoms were older and less likely to
have a pathologic pH-value or manometry
result or a hiatus hernia. These results seem
to confirm the existence of gender-specific dif-
ferences in the severity of reflux esophagitis.
Comparing patients with BE, women were sig-
nificantly older than men. Furthermore, in
men, the duration of reflux symptoms was sig-
nificantly longer. No gender-specific differences
were found for acid or bile reflux, prevalence
and size of hiatus hernia and function of the
gastroesophageal sphincter.
Falk et al. [36] investigated patients who had
been included on the BE register in Cleveland,
Ohio between 1979 and 2002 (n = 839). They
looked at age, gender, race, extent of BE, hiatus
hernia and histological results [36]. The ratio
between men/women was 3/1 for BE. Addition-
ally, the length of BE was significantly shorter
in women. The prevalence of high-grade dys-
plasia and carcinomas was twice as high in
men compared to women. Women with high-
grade intraepithelial neoplasias and carcino-
mas tended to be older than men. While the
incidence of high-grade intraepithelial neopla-
sias and carcinomas showed no gender-specific
differences, this was mostly due to having a
small study group [36].
In another study, of 22,000 patients, the
gender ratio for men/women was 4.15/1 with
a similar increase in prevalence between the
ages of 20 and 59 years in men and between 20
and 79 years in women [38]. In both genders,
the BE incidences ran in parallel. However, an
age shift of 20 years was seen for both groups.
These findings have been confirmed by other
studies [39]. A decreasing incidence of BE in
men that were older than 59 years resulted in a
total incidence ratio for men/women of 2/1.
The mean age at diagnosis of adenocarcinoma
was 64.7 � 8.2 years in men and 74.0 � 8.5
years in women. The gender ratio of 4.15/1
men/women in the 20–59 year agegroup might
Review
be one reason for the higher prevalence of
adenocarcinoma in men compared to women.
Conclusion
Male gender is a clear risk factor in the pre-
valence and onset of GERD and BE. Addition-
ally, a more serious course is found for both
diseases in men. Concerning quality-of-life,
recently published data have demonstrated
that patients with BE have a higher health-
related quality-of-life compared to patients
suffering from GERD, probably due to reduced
symptom severity [40]. There was no additional
decrement in health-related quality-of-life
because of perceived cancer risk or fear of
developing or dying from cancer. Female gen-
der was associated with a worsened health-
related quality-of-life regardless of GERD dis-
ease manifestation.
For clinical practice, further large prospec-
tive studies are warranted to provide strategies
on how to best handle gender-specific differ-
ences when patients are diagnosed with GERD
or BE. Knowledge of the gender-specific differ-
ences in reflux disease and BE may be helpful
for improving surveillance and screening stra-
tegies, although distinct recommendations are
lacking so far.
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