H.

pylori and functional dyspepsia: Increased serum

antibodies as an independent risk factor?
Abstract (summary)
The relationship between H. pylori and functional dyspepsia is controversial. Hypothesizing
that subjects with a more intense immune response to H. pylori (and hence higher antibody
titers) would be at greater risk of dyspepsia, we aimed to identify risk factors for the
development of dyspeptic symptoms. In all, 491 healthy blood donors with no history of
peptic ulceration and 74 consecutive patients with a confirmed diagnosis of functional
dyspepsia were studied. Symptoms and potential risk factors [nonsteroidal antiinflammatory
drugs (NSAIDs), alcohol, and smoking] were measured by a validated questionnaire. H.
pylori status was determined by IgG antibodies using a validated ELISA test with a cutoff
titer for a positive serology of 10 units/ml. Logistic regression analysis assessed the
association between risk factors and dyspepsia. Among blood donors, 21% (95% CI 17.624.8) reported dyspepsia (pain localized to the upper abdomen); 7.7% (95% CI 5.5-10.4) had
frequent dyspepsia (>6 times in the prior year). The age-adjusted prevalence of H. pylori was
not significantly different in blood donors with (39.5%, 95% CI 24.0-56.6) and without
frequent dyspepsia (34.2%, 95% CI 29.8-38.36), but was significantly greater in patients with
functional dyspepsia (68.8%, 95% CI 57.3-77.9). In the combined study population of blood
donors and patients with functional dyspepsia, logistic regression adjusting for age identified
the following independent risk factors for frequent dyspepsia: high serum antibody levels
against H. pylori (OR for IgG titer >50 units/ml vs H. pylori titers 11-50 units/ml 4.6, 95% CI
2.7-7.8) and consumption of standard NSAIDs (OR 2.4,95% CI 1.3-4.5). In contrast, alcohol
(OR 0.6, 95% CI 0.3-1.0), smoking (OR 1.5, 95% CI 1.0-2.3) or positive H. pylori serology
with titers < or = 50 units/ml (OR 1.6, 95% CI 0.8-2.9) were not associated with frequent
dyspepsia. In conclusion, in a subgroup of H. pylori-infected subjects who have high
antibody titers, H. pylori appears to be associated with functional dyspepsia.
Headnote
The relationship between H. pylori and functional dyspepsia is controversial. Hypothesizing
that subjects with a more intense immune response to H. pylori (and hence higher antibody
titers) would be at greater risk of dyspepsia, we aimed to identify risk factors for the
development of dyspeptic symptoms. In all, 491 healthy blood donors with no history of
peptic ulceration and 74 consecutive patients with a confirmed diagnosis of functional
dyspepsia were studied. Symptoms and potential risk factors [nonsteroidal antiinflammatory
drugs (NSAIDs), alcohol, and smoking] were measured by a validated questionnaire. H.
pylori status was determined by IgG antibodies using a validated ELISA test with a cutoff
titer for a positive serology of 10 units/ml. Logistic regression analysis assessed the
association between risk factors and dyspepsia. Among blood donors, 21% (95% CI 17.6
-24.8) reported dyspepsia (pain localized to the upper abdomen); 7.7% (95% CI 5.5-10.4) had
frequent dyspepsia (.6 times in the prior year). The age-adjusted prevalence of H. pylori was
not significantly different in blood donors with (39.5%, 95% CI 24.0 -56.6) and without
frequent dyspepsia (34.2%, 95% CI 29.8 -38.36), but was significantly greater in patients
with functional dyspepsia (68.8%, 95% CI 57.3-77.9). In the combined study population of
blood donors and patients with functional dyspepsia, logistic regression adjusting for age
identified the following independent risk factors for frequent dyspepsia: high serum antibody

levels against H. pylori (OR for IgG titer .50 units/ml vs H. pylori titers 11-50 units/ml 4.6,
95% CI 2.7-7.8) and consumption of standard NSAIDs (OR 2.4, 95% CI 1.3- 4.5). In
contrast, alcohol (OR 0.6, 95% CI 0.3-1.0), smoking (OR 1.5, 95% CI 1.0 -2.3) or positive H.
pylori serology with titers #50 units/ml (OR 1.6, 95% CI 0.8 -2.9) were not associated with
frequent dyspepsia. In conclusion, in a subgroup of H. pylori-infected subjects who have high
antibody titers, H. pylori appears to be associated with functional dyspepsia.
KEY WORDS: functional dyspepsia; H. pylori; ELISA; smoking; alcohol; nonsteroidal
antiinflammatory drugs.
The majority of patients with chronic or recurrent dyspepsia do not have a peptic ulcer, reflux
esophagitis, or gastric cancer, but are categorized as having functional (or nonulcer)
dyspepsia (1). Whether gastritis accounts for dyspeptic symptoms in patients with otherwise
unexplained dyspepsia remains controversial. It is now accepted that H. pylori is the most
important cause of chronic histologic gastritis (2). Between 30% and 70% of patients with
functional dyspepsia have H. pylori infection, and it has been suggested that infection with H.
pylori may represent the pathophysiological basis for the development of symptoms in at
least a proportion of these cases (3- 6). However, there is only equivocal evidence for a role
of H. pylori in functional dyspepsia based on epidemiological and treatment studies (2-5, 7,
8). It is conceivable, on the other hand, that only a subgroup of patients infected with H.
pylori are at risk of developing dyspepsia. For example, there may be different strains of H.
pylori that produce specific virulence factors (9), while host factors may modulate the effects
of H. pylori (10). The inflammatory response of the gastric mucosa to H. pylori infection may
be mirrored by the level of H. pylori antibody titers (11). We postulated that those who fail to
properly downregulate the infection (as reflected by higher antibody titers to the infection)
would be more prone to developing symptoms.
Whether environmental factors such as consumption of standard nonsteroidal
antiinflammatory drugs (NSAIDs), alcohol, or smoking alter the host response to H. pylori is
unknown. Studies assessing the association between H. pylori and dyspepsia have not usually
controlled for these concomitant risk factors. Alcohol and smoking have not been found to be
risk factors for functional dyspepsia (12, 13), but the role of NSAIDs remains controversial
(13, 14).
In the present study, therefore, we aimed to identify risk factors for the development of
dyspeptic symptoms in an unselected population of patients and blood donors with chronic
unexplained dyspepsia. The following factors were tested: intensity of the immune response
to H. pylori infection (as measured by antibody titers), consumption of alcohol, NSAID use,
and smoking.
MATERIALS AND METHODS
Subjects. After approval of the experimental protocol by the Institutional Review Board of
the University of Essen, 491 consecutive healthy persons [34.1 6 10.9 years old (mean 6 SD)
range 18-65; 59% men] without a history of peptic ulcer or other gastrointestinal disease who
volunteered to provide an unpaid blood donation were included in the study. After giving
informed consent, all volunteers underwent a physical examination and laboratory screening
(sedimentation rate, red and white blood count, transaminases, g-glutamyltransferase,
hepatitis B and C antibodies, and HIV antibodies) that was normal.

The second group comprised 78 consecutive patients with a final diagnosis of functional
dyspepsia who had symptoms for at least six months. Sixty patients were recruited for this
study by four internists and gastroenterologists in private practice. Standard diagnostic workup was performed in all patients and the diagnosis of functional dyspepsia was confirmed.
The remaining eighteen patients directly presented to our institution for evaluation and
treatment. The median interval between the first manifestation of symptoms and inclusion
into the study was 48 months. In all patients, diagnostic work-up included physical
examination, laboratory testing (ie, white and red blood count, sedimentation rate, fasting
blood sugar, liver function tests), abdominal sonography, upper gastrointestinal endoscopy,
and 24-hr esophageal pH measurement; all patients over 35 years of age also had a
colonoscopy performed. Within three working days of confirming the diagnosis, all patients
presented to the study center. The medical history was taken and the charts were reviewed by
one of the authors (G.H.). Two patients had only minor complaints at presentation (symptoms
had spontaneously improved), one patient had a history of peptic ulcer disease, and one
patient reported that H. pylori eradication treatment had been given three months previously;
these patients were excluded. A total of 74 patients with a final diagnosis of functional
dyspepsia were therefore enrolled (41.4 6 13.6 years old range 18-74 years; 52.4% women).
Determination of H. pylori Status. In all subjects, 10 ml of blood was taken for the
determination of Helicobacter pylori antibodies (Elias, Freiburg, Germany). The preparation
of the antigen used for this commercially available assay was performed according to the
method described by Blaser and Duncan (15). Previous studies have shown that the
serodiagnosis of H. pylori is highly sensitive and specific (16). Compared with the
combination of urease (CLO) testing, histology, and microbiological culture, the sensitivity
and specificity of the present assay were 94% and 88%, respectively, in a study population of
104 patients tested in our laboratory (14). Titers (by optical density) above 10 units/ml were
considered to be positive. In addition, a titer .50 units/ml was defined a priori as a high titer,
since 50% of a previously reported sample of H. pylori-infected blood donors had thresholds
below this value (14).
Assessment of Abdominal Symptoms. A German version of the previously validated Bowel
Disease Questionnaire (BDQ) (14, 17) was filled in by all study participants. This
questionnaire assessed abdominal symptoms, current or past gastrointestinal disease (eg,
peptic ulcer), and previous surgery. It was completed prior to the physical examination. The
German version of the questionnaire has been used in population-based studies (14, 18) and
has good reliability and validity (19 -22).
Selection of Questionnaire Items. Standardized criteria were utilized for the categorization of
symptoms based on previous studies (20 -23). Briefly, subjects who reported pain centered in
the upper abdomen during the previous year were classified as having dyspepsia; those with
pain more than six times during the last year were considered to have frequent dyspepsia
(24). The subjects were also categorized into one of three symptom subgroups based on their
responses on the BDQ, as has been applied in previous studies.
Category 1 included those with ulcerlike symptoms. Subjects had upper abdominal pain and
at least two of the following symptoms (22, 23): (1) pain often relieved by food (.25% of the
time); (2) pain often relieved by antacids; (3) pain often before meals or when hungry; (4)
periodic pain (periods of at least one month without pain, with periods in between of weeks
to months when there is pain); and/or (5) night pain (waking the subject from sleep).

Category 2 included those with dysmotility-like dyspepsia (22, 23). Patients had upper
abdominal pain and at least three or more of the following symptoms suggesting gastric stasis
or upper intestinal dysmotility: (1) nausea or vomiting once a month or more; (2) abdominal
bloating and visible distension often; (3) anorexia or weight loss (.3.5 kg); (4) pain often
aggravated by food or milk; (5) pain often after meals; and/or (6) pain often relieved by
belching.
Category 3 included those with refluxlike dyspepsia (1, 22, 23). These patients had upper
abdominal pain associated with one or more of the following symptoms: (1) heartburn at least
once a week or more and/or (2) acid regurgitation once a week or more.
Smoking habits, weekly consumption of alcoholic beverages as well as intake of analgesics
(aspirin and NSAIDs) were assessed by the standardized questionnaire. In addition, the
reasons for taking any analgesics were recorded. Acetaminophen was not considered in the
analyses (20).
Statistical Analyses. Prevalence rates and the respective 95% confidence intervals were
calculated (25). The frequency of positive H. pylori titers (.10 units/ml) in different study
groups (blood donors without dyspepsia or with infrequent dyspepsia and blood donors and
patients with frequent dyspepsia) were compared with Fisher's exact x2 test, stratified for
different age groups (,35 and $35 years old). Alcohol consumption of more than six alcoholic
beverages per week was considered frequent alcohol consumption. All subjects that currently
reported smoking cigarettes were classified as smokers. In addition, subjects were
categorized into those without any consumption of aspirin or NSAIDs, and those reporting
consumption of at least one tablet per week. A negative H. pylori titer was #10 units/ml (14).
Based on previous studies, a low titer was considered to be present if it was between 11 and
50 units/ml and a high titer was above this threshold (14). H. pylori titers were coded 0 (titer
10 units/ml), 1 (titer 11-50 units/ml), and 2 (titer .50 units/ml). Other risk factors were coded
as present or absent. In the combined sample of blood donors and patients with a diagnosis of
functional dyspepsia, we assessed in the first step the univariate association between frequent
dyspepsia (ie., symptoms .6/yr or patient status) and H. pylori, NSAIDs, frequent alcohol, and
smoking. All variables significantly associated with frequent dyspepsia were included in a
logistic regression analysis adjusting for age and gender. Similarly, the association between
H. pylori titer strata and age, frequent alcohol consumption, smoking, and intake of NSAIDs
was evaluated using logistic regression. All P values calculated were two-tailed; an a-level of
5% was considered significant. Statistical analyses were performed using the Statistical
Analysis System (26).
RESULTS
Dyspeptic Symptoms in the Population. One hundred four blood donors (21%, 95% CI 17.6
-24.8) reported dyspepsia (pain or discomfort localized to the upper abdomen, postprandial
fullness) and 38 subjects (7.7%, 95% CI 5.5-10.4) were categorized as having frequent
dyspepsia (symptoms localized to the upper abdomen and occurring more than six times in
the prior 12 months).
All patients with functional dyspepsia had symptoms during the prior 12 months; 72 of 74
(97.3%, 95% CI 90.6 -99.7) were categorized as having frequent dyspepsia. The
sociodemographic characteristics of the blood donors with and without dyspeptic symptoms
and patients with functional dyspepsia are shown in Table 1.

Prevalence of H. pylori Infection and Dyspeptic Symptoms. Prevalence rates of H. pylori in

patients with functional dyspepsia and the control population of blood donors are depicted in
Figure 1. One hundred seventy of 491 blood donors (34.6%, 95% CI 30.4 -38.8) were H.
pylori-positive. In contrast, the H. pylori prevalence in patients with functional dyspepsia was
68.8% (95% CI 57.3-77.9). This difference in the H. pylori prevalence was significant versus
the blood donors adjusting for age, gender, and socioeconomic status (P , 0.001). In blood
donors with and without dyspepsia and patients with functional dyspepsia, there was a
significant correlation (r . 0.8, P , 0.001) between age and H. pylori prevalence, with a mean
annual increase of the H. pylori prevalence of 1.2 6 0.4% in blood donors and 1.4 6 0.5% in
patients with functional dyspepsia (P . 0.6).
In patients with functional dyspepsia, 52.8% (95% CI 40.7- 64.7) had an IgG titer .50
units/ml compared to 14.8% (95% CI 11.7-18.0) of blood donors without dyspepsia (P ,
0.05). Similarly, in blood donors with frequent dyspepsia the proportion of subjects with high
titers was greater (21.0%, 95% CI 9.6 -37.3) than those without dyspepsia (13%, 95% CI 10.0
-16.8), although this difference failed to reach statistical significance (P . 0.2). H. pylori titers
were not associated with smoking, alcohol consumption, or intake of aspirin or nonaspirin
NSAIDs. Analyzing the combined samples of blood donors and patients with functional
dyspepsia, the proportion of subjects with H. pylori titers above 50 units/ml was significantly
higher in subjects with frequent dyspepsia as compared to subjects without frequent
dyspepsia (Figure 2).
H. pylori and Symptom Subgroups. Based on the symptoms as assessed by the BDQ, patients
with functional dyspepsia and blood donors with frequent dyspepsia were categorized as
having dysmotility-like (93.2%, 95% CI 86.5-97.29), refluxlike (79.6%, 95% CI 71.8-87.4),
and ulcerlike dyspepsia (69.7%, 95% CI 61-78.8, Figure 3). As expected, there was very
substantial overlap of these groups. There was no significant difference in the H. pylori titers
among patients with functional dyspepsia and blood donors with ulcerlike, dysmotility-like,
and refluxlike dyspepsia (58 6 8, 62 6 10 and 60 6 8 units/ml, respectively, P . 0.6).
Risk Factors for Development of Symptoms. Univariate analysis identified consumption of
NSAIDs and a H. pylori titer above 50 units/ml as significant risk factors for dyspepsia.
Logistic regression analysis, adjusting for age and gender, identified two significant risk
factors for frequent dyspepsia: consumption of NSAIDs (including aspirin) (OR 2.4, 95% CI
1.3-4.5), and high H. pylori IgG titers (OR for IgG titer .50 units/ml vs H. pylori-negative
subjects 4.6, 95% CI 2.7-7.8; and OR for IgG titer .50 units/ml vs 11-50 units/ml 2.9, 95% CI
1.5-5.6). In contrast, H. pylori infection with IgG titers of 11-50 units/ml were not
significantly associated with frequent dyspepsia (OR 1.6, 95% CI 0.8 -2.9). It is noteworthy
that the risk for frequent dyspepsia increased 14-fold (95% CI 3.4 -58.1) in subjects who
simultaneously had high H. pylori titers and consumed NSAIDs as compared to H. pylorinegative subjects who did not consume NSAIDs (Figure 4). Consumption of alcohol (OR 0.6,
95% CI 0.3-1.0) and smoking (OR 1.5, 95% CI 1.0-2.3) were not significantly associated
with frequent dyspepsia. The reasons (more than one answer was allowed) for consumption
of analgesics were headache (80%), menstrual pain (21%), or both (13%); 9% reported use of
NSAIDs for joint or back pain. No patient or blood donor reported consumption of analgesics
for abdominal pain. The reasons for consumption of analgesics were similar in patients with
functional dyspepsia and blood donors with frequent dyspepsia.
DISCUSSION

H. pylori is highly prevalent in the general population, and the majority of infected subjects
have no symptoms. Whether treatment targeted against H. pylori is justified in subjects with
otherwise unexplained chronic dyspepsia is a matter of debate. Only equivocal evidence for a
role of H. pylori has come from treatment studies. Most recent high-quality trials have been
negative (27-29), although in one study (30) a beneficial effect was observed of H. pylori
eradication in functional dyspepsia. It has been argued that treatment may confer other
general benefits (eg, elimination of an undiagnosed ulcer diathesis), but the cost effectiveness
of therapy is not established. Indeed, even if treatment of the infection is of benefit in a small
subset, there have been no indicators that allow clinicians to predict who may be more likely
to respond.
In the present study, we analyzed potential risk factors for the development of dyspepsia and
found that the risk was four times higher in H. pylori infected subjects with high antibodies
titers, adjusting for confounders such as age. In contrast, the risk of dyspepsia in H. pyloriinfected subjects with low IgG antibody titers was not significantly increased. Furthermore,
H. pylori infection was not associated with any specific pattern of symptoms, confirming
previous findings (14). A second risk factor for dyspepsia was consumption of traditional
NSAIDs, where the risk of dyspepsia was two times higher. It needs to be emphasized that in
H. pylori-positive subjects, the risk of having frequent dyspepsia was further increased by
consumption of NSAIDs. In subjects consuming NSAIDs with high H. pylori antibody titers,
there was a 14-fold increased risk of having frequent dyspepsia compared to subjects not
consuming NSAIDs who had a negative H. pylori titer.
The prevalence of infection with H. pylori was higher in patients with functional dyspepsia
compared to the blood donor population. The higher prevalence of infection could not be
explained by the age differences between patients and controls. Patients with functional
dyspepsia were on average 7 years older than the blood donors, but after adjusting for age as
well as socioeconomic status the prevalence of H. pylori was still significantly (P , 0.001)
increased in patients with functional dyspepsia. It is conceivable that this increased
prevalence of H. pylori is explained by selection bias. However, as we recruited consecutive
outpatients that were referred for evaluation and treatment to a tertiary referral center as well
as patients that presented to gastroenterologists in private practice who do not require general
practitioner referral, we are confident that the patients are reasonably representative of
functional dyspepsia in specialist care. Virtually all subjects in the population have private or
public health insurance, and thus lack of health insurance should not have resulted in
selection bias in our population.
The majority of H. pylori-infected subjects are known to be asymptomatic. This has led to the
speculation that if H. pylori causes dyspepsia, then differences in bacterial virulence or
differences in the host response to H. pylori infection must serve as an explanation for the
occurrence of symptoms in these patients (9). Our data suggest, for the first time, that the
intensity of the immune response to H. pylori as measured by IgG antibodies is a marker for
the risk of having symptoms in H. pylori infection. Factors that induce a high antibody titer to
H. pylori remain incompletely understood, and indeed a greater humoral response may not
reflect more severe gastric inflammation but rather individual differences in the immune
response. Alternatively, the virulence of various H. pylori strains may be important. Even
though there has been intense interest in putative bacterial virulence factors in the
pathogenesis of gastritis, it still is uncertain whether the factors identified represent cause and
effect. A vacuolating toxin, for example, has been found in approximately 50% of H. pylori
strains that is linked to a more intense gastric inflammation (31, 32). However, to date an

association between cytotoxin-producing H. pylori strains and functional dyspepsia has not
been established(33).
Although increased H. pylori titers were associated with dyspepsia, a number of
asymptomatic subjects had high H. pylori titers. This emphasizes that multiple factors are
likely to determine whether symptoms occur. There is clear evidence that functional
dyspepsia is a heterogeneous, multifactorial disease. Functional disturbances, such as gastric
motor disorders or sensory defects, can be found in a proportion of subjects (34). It is
possible that H. pylori infection only results in symptoms in that group of subjects who have
certain permissive characteristics such as gastric visceral hypersensitivity. It has been well
demonstrated that a subgroup of patients with functional dyspepsia has lowered gastric (35,
36) and intestinal sensory thresholds (37, 38). Although the presence of H. pylori was not
associated with lower gastric perception thresholds in one study (39), in a previous study we
found lowered duodenal sensory thresholds in subjects with high antibody titers (40). Thus,
gastric inflammation may reset sensory perception pathways in the spinal cord or brain in
predisposed individuals who manifest higher titers, and even if the infection is eliminated
symptoms do not resolve. This clearly could explain the negative results of the H. pylori
eradication trials (27-29). Indeed, in recent animal studies, an acute inflammation of the colon
induced visceral hyperalgesia that persisted even after complete resolution of the
inflammation (41).
The prevalence of peptic ulcers in an Italian population of asymptomatic H. pylori-positive
blood donors was reported to be 21% (42). It thus might be argued that the association
between H. pylori and frequent dyspepsia in our blood donors could simply be due to
unrecognized peptic ulcer disease. However, in the Italian study population of 1010 blood
donors who were screened, only 180 were tested further and an even smaller group was
endoscoped (42). The 2% prevalence of gastric malignancies observed in this study was also
higher than would have been expected. Furthermore, past peptic ulcer was not an exclusion
criteria in the Italian blood donors. Thus, it is likely that the high prevalence rate of peptic
ulcer disease was at least partially due to selection bias. In our population of blood donors, a
history of peptic ulcer disease was grounds for exclusion (as required by the federal
regulations for blood donations in Germany). Moreover, we found no association between the
overall presence of H. pylori and dyspepsia in the blood donors, which would not be expected
if many had H. pylori ulcers. A recent endoscopy study from Texas found that peptic ulcer
was only detected in 1% of healthy subjects (43). Thus it is unlikely that the association
between high H. pylori titers and frequent dyspepsia is explained by unrecognized peptic
ulcer disease in the blood donor volunteers.
In summary, we found that H. pylori was associated with frequent dyspepsia in a subgroup of
H. pyloriinfected subjects who had a more intense immune response to H. pylori as reflected
by increased IgG titers. In contrast, we observed no association between H. pylori and
frequent dyspepsia in H. pyloriinfected subjects who lacked high antibody titers. The
applicability of this potential disease marker in functional dyspepsia needs prospective
validation.
ACKNOWLEDGMENTS
The authors appreciate the continuous cooperation of the following physicians who referred
patients for this study: Dr. A. Boekstegers; Dr. A. Pariwar; Dr. H. Ru -menapf; Dr. L. Schlo
mann; Dr. T. Thomas. The skillful assistance of Ms. Jutta Neufang-Hu ber is greatly

appreciated. The authors are indebted to the staff, technicians, and nurses of the Department
of Transfusion Medicine for their support.
This work was supported by a grant from the German Research Foundation, grant Ho 1193/32.
Sidebar
Digestive Diseases and Sciences, Vol. 46, No. 7 (July 2001), pp. 1550-1557
0163-2116/01/0700-1550$19.50/0 (C) 2001 Plenum Publishing Corporation
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