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Eradication of Helicobacter pylori May Be Beneficial in the Management of Chronic Open-Angle Glaucoma
Jannis Kountouras, MD, PhD;
Nikolaos Mylopoulos, MD, PhD;
Dimitrios Chatzopoulos, MD;
Christos Zavos, MD;
Panagiota Boura, MD, PhD;
Anastasios G. P. Konstas, MD, PhD;
John Venizelos, MD, PhD
Arch Intern Med. 2002;162:1237-1244.
ABSTRACT
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Background We have documented a high prevalence of Helicobacter
pylori infection in patients with glaucoma.
Objective To evaluate the effect of H pylori eradication
on the 2 most commonly used glaucoma parameters: intraocular pressure and
visual field.
Methods A total of 41 patients with glaucoma and 30 age-matched anemic controls
underwent upper gastrointestinal endoscopies and gastric mucosal biopsies
to detect the presence of H pylori infection by histologic
analysis and rapid urease test (CLOtest; Delta West, Draper, Utah). Saliva
samples were also tested by CLOtest. Serum anti–H
pylori–specific IgG was analyzed by enzyme-linked immunosorbent
assay. Helicobacter pylori–positive patients
received a triple eradication regimen (omeprazole, clarithromycin, and amoxicillin
treatment), and all patients were observed for 2 years while remaining under
the same antiglaucoma therapy.
Results Helicobacter pylori was detected in 88% of
glaucoma cases and in 47% of controls (P<.001). Helicobacter pylori eradication was successful in 83% of
treated patients. At the 2-year clinical end point, glaucoma parameters (mean
intraocular pressure and mean visual field parameters) were improved in the
subgroup of patients where H pylori eradication was
successful (P<.001 for intraocular pressure; P .01 for visual field parameters), but not in the other
patients.
Conclusion Helicobacter pylori eradication may positively
influence glaucoma parameters, suggesting a possible causal link between H pylori and glaucoma.
INTRODUCTION
GLAUCOMA COMPRISES a large group of age-related disorders characterized
by widely diverse clinical and morphological manifestations.1
The common characteristic of all forms of glaucoma is progressive optic neuropathy,
which derives from a multitude of risk factors. Recently, it has become clear
in animal models of glaucoma that retinal ganglion cells die via apoptosis.2 Currently, the best-known causative risk factor is
raised intraocular pressure.1 Other less well-understood
risk factors include ischemia, vascular dysregulation, and low systemic blood
pressure.2-3 These factors induce
ocular blood flow deficits that either cause direct damage or increase the
susceptibility of the neural tissue in the optic nerve. Recent evidence suggests
that glaucomatous optic neuropathy may be associated with changes in endothelium-dependent
vascular regulation, impaired ocular blood flow, and cytokines.3
Glaucoma is currently the second most common cause of blindness in the
world.1, 4 Although glaucoma-related
loss of vision cannot be reversed in adult patients, blindness can be prevented
in nearly all cases with early detection and proper therapy.4
Nevertheless, the only available therapeutic intervention in glaucoma remains
the reduction of intraocular pressure by topical drugs, laser treatment, or
surgery,4 and this approach fails to address
the events leading to the elevated intraocular pressure. A far more effective
goal in the treatment of glaucoma might be to address the various risk factors
leading to glaucomatous neuropathy. However, appropriate management of glaucoma
requires a better understanding of the pathogenetic mechanisms involved.
Helicobacter pylori is a curved spiral gram-negative
bacterium that colonizes the gastric mucosa of most humans worldwide, mainly
affecting older adults in the developed world, including Greece.5-6
It is associated with various upper gastrointestinal (GI) diseases5, 7 and has also been implicated in a variety
of extradigestive vascular conditions including ischemic heart disease,8 ischemic cerebrovascular disorders,9
and functional vascular disorders caused by vascular dysregulation (eg, Raynaud
phenomenon and migraine)10 and with some autoimmune
conditions such as Sjögren syndrome.11
Until now, no attempt has been made to investigate the prevalence of H pylori in glaucoma patients. Only recently, Kountouras
and associates12 reported a higher prevalence
of H pylori in Greek patients with open-angle glaucoma
(OAG) than in age-matched controls, suggesting for the first time an association
between H pylori infection and glaucoma in this ethnic
cohort. Demonstrating the association of H pylori
and glaucoma and proving the benefit of eradicating H pylori in the clinical course of the disease may have a major impact on treatment.
Nevertheless, before antibiotic therapy for H pylori
infection becomes an established step in the management of chronic OAG, sufficient
evidence must be provided that glaucoma parameters are positively influenced
by the eradication of H pylori infection.
The objective of the present study is to evaluate the effect of H pylori eradication on 2 well-established clinical parameters
in glaucoma: intraocular pressure and visual field indices.13
We have therefore designed methods to confirm and quantify our hypothesis
that H pylori eradication therapy has a beneficial
effect on these 2 glaucoma parameters in H pylori–positive
patients with glaucoma.
PATIENTS AND METHODS
PATIENTS
This was a 2-part study. Part 1 was designed to evaluate the prevalence
of H pylori infection in chronic OAG.12
Forty-one patients with documented chronic OAG and 30 age-matched anemic controls
were included in this part of the study. The control subjects were undergoing
upper and lower GI endoscopy to investigate mild iron-deficiency anemia, but
their endoscopy findings were normal. After a detailed history was taken from
all patients and their first-degree relatives, 26 (63%) patients with glaucoma
were found to have intermittent symptoms of dyspepsia (defined as pain, discomfort,
or other symptoms believed to originate from the upper GI tract), heartburn,
or a history of upper GI tract bleeding. All patients with glaucoma (36 H pylori–infected patients who received the H pylori eradication regimen and 5 H
pylori–negative patients who did not receive eradication therapy)
were subsequently observed in the second part of the study, which evaluated
the effect of administration of H pylori eradication
regimen on intraocular pressure and visual field parameters over a 2-year
follow-up period.
Patients were enrolled in the study if they met the following criteria:
(1) an untreated intraocular pressure of 21 mm Hg or higher; (2) typical glaucomatous
optic nerve head changes (including saucerization, rim thinning or notching
in the inferior or superior temporal area of the optic nerve head, or total
glaucomatous cupping)12; and/or (3) typical
glaucomatous visual field loss (including a paracentral, arcuate, or Seidel
scotoma or a nasal step).12 Seven of the patients
enrolled were legally blind in the contralateral eye due to end-stage glaucoma.
To reduce the possible bias of age, all participants were older than 45 and
younger than 70 years. Exclusion criteria included all eye diseases other
than glaucoma, diabetes mellitus, and a myopic refractive error exceeding -8
diopters. In addition, patients were excluded if they had taken H2-receptor
antagonists, proton pump inhibitors, antibiotics, bismuth compounds, or nonsteroidal
anti-inflammatory drugs in the preceding 4 weeks (excluding low doses of aspirin
[ie, 80 mg 2-3 times daily]). Patients were also excluded if they had undergone
previous gastric surgery; were receiving anticoagulant therapy; were alcohol
abusers; had allergy to penicillin or macrolides; had gastric cancer or other
neoplasms; or had severe cardiac, pulmonary, kidney, or liver disease.
All patients signed a consent form prior to enrollment, and the study
protocol was approved by the local ethics committee. The intraocular pressure
was measured with a calibrated Goldmann applanation tonometer by the same
ophthalmologist. The visual field parameters were measured with the G1 Octopus
program (Octopus 500EZ G1; Luterzeag AG, Zurich, Switzerland) by the same
perimetrist. The ophthalmologist and the perimetrist were masked to the H pylori status of the patient. All patients had prior
experience with automated perimetry. The parameters assessed included corrected
loss variance (CLV), mean defect (MD), and short-term fluctuation (SF) of
both eyes. The G1 program evaluates the threshold at 59 points within the
central 30° of the visual field. Normal intraocular pressure generally
varies between 12 and 20 mm Hg.12 The normal
spread of the visual field parameters are SF, 0 to 2 dB; CLV, 0 to 4 dB; and
MD –2 to +2 dB.12 The SF describes the
intratest variation of the retinal sensitivity and may be affected by test-retest
experience. The CLV shows the nonuniform variation from the expected hill
of vision minus the effect of the SF. The MD represents the average decibel
defect per location from the expected norm and may be influenced by refraction,
the pupil size, and media opacities. It should be emphasized that no definite
rules exist to indicate whether a patient's condition is progressing or is
stable.
Only topical glaucoma treatment was used in the 41 patients included
in this study. The details of their treatment have been reported previously.12 None of the patients in this study received oral
drugs that could influence intraocular pressure (eg, carbonic anhydrase inhibitors).
All patients with glaucoma received the same topical eye regimen during the
2-year follow-up period of this study.
The control subjects had been recently diagnosed as having mild iron-deficiency
anemia. The diagnosis of anemia was based on history and the GI investigation,
and none of the subjects had received any treatment (eg, ferrous sulfate)
prior to the diagnosis. The details of the their blood profile and the causes
of iron-deficiency anemia have been reported previously.12
All 71 participants (41 patients with glaucoma, 30 anemic controls)
underwent elective upper GI endoscopy combined with diagnostic biopsies at
baseline. In addition, all patients with glaucoma underwent the same endoscopic
procedure 3 months after H pylori–eradication
treatment. Patients with peptic ulcer disease who agreed to undergo repeated
elective follow-up endoscopies with biopsies were followed up with elective
endoscopic procedures at 6 and 12 months to rule out H pylori reinfection.
STUDY DESIGN
Subjects reported for the procedures at 9 AM after a 12-hour fast. Intravenous
sedation was given, and standard upper GI endoscopy was performed with a forward-viewing
videoscope (Olympus CE 0197; Opto-Electronics Co Ltd, Tokyo, Japan) for evaluation
of any macroscopic abnormalities. Simultaneously, 3 biopsy specimens were
obtained from the antral region within 2 cm of the pyloric ring and 3 from
the corpus. A biopsy specimen from each site was used for rapid urease slide
testing for H pylori infection (CLOtest; Delta West,
Draper, Utah), and the other 2 biopsy specimens were placed in 10% formalin
and submitted for histologic examination. Before endoscopy, venous blood was
drawn from each patient for serologic testing for H pylori IgG antibodies. Serum samples were stored at –20°C for analysis
within 20 to 25 days for H pylori IgG antibodies
by using an enzyme-linked immunosorbent assay technique (Elias, Osceola, Wis).
Simultaneously, saliva samples were also collected in sterile tubes for rapid
urease activity testing. To prevent contamination of specimens from different
sites, biopsy specimens from each site were taken with a fresh pair of sterile
forceps. The forceps were wiped with alcohol on withdrawal from the endoscope
to remove any organism that might have been present in the biopsy channel.
Endoscopes were sterilized between procedures according to standard guidelines.14
BIOPSY AND SALIVA UREASE TESTS
Each biopsy specimen and saliva sample was placed in a tube containing
0.5 mL of 10% urea in deionized water to which had been added 2 drops of 1%
phenol red as a pH indicator (CLOtest). The biopsy specimen test was read
at 5 minutes, 1 hour, 3 hours, and 24 hours and was considered positive if
the indicator changed from yellow to red at any time. The saliva sample test
was read at 5 minutes, 1 hour, and 3 hours.12, 15
HISTOPATHOLOGIC ANALYSIS
All specimens were stained with hematoxylin-eosin and Crezyl fast violet
and/or Giemsa stain (for detection of H pylori organisms).
The presence of gastritis was classified in accordance with the Sydney System
and included assessment of atrophy grade, chronicity, activity, and intestinal
metaplasia on a scale of 0 (absent) to 3 (high), as previously reported.12 In particular, intestinal metaplasia was evaluated
with Alcian blue stain in addition to hematoxylin-eosin. The same experienced
pathologist, masked to the other determinants of H pylori status and to the patients' group, assessed all specimens.
H PYLORI SEROLOGIC TESTING
Helicobacter pylori serologic status was determined
by using a commercial enzyme-linked immunosorbent assay kit (Elias). The manufacturer's
recommended cutoff value of 10 U/mL for H pylori
IgG, validated in our laboratories, was used to define patient serologic findings
as positive or negative.
The diagnosis of H pylori infection was based
on histologic findings. In particular, H pylori infection
was assumed when active gastritis with bacteria of typical shape was found
histologically. Other parameters used were positive CLOtest findings (biopsy
specimens and saliva) and H pylori IgG serologic
results.
TREATMENT OF H PYLORI INFECTION
To treat H pylori infection, a 1-week course
of omeprazole (20 mg twice a day), clarithromycin (500 mg twice a day), and
amoxycillin (1 g twice a day) was given followed by 20 mg of omeprazole daily
for 1 month. The patients completed a questionnaire to record the adverse
effects occurring during treatment and their compliance with the therapy.
The adverse effects were recorded as absent, mild, moderate, or severe. Compliance
was evaluated by counting tablets and capsules after therapy: good compliance
was ensured when the patient had taken more than 90% of the tablets and capsules.
FOLLOW-UP SCHEME
Success of the H pylori eradication regimen
was evaluated by control endoscopy at least 8 weeks after cessation of therapy,
and we considered a patient to be H pylori negative
if both histologic and the rapid urease test results were negative. Exclusion
of H pylori reinfection was determined in patients
with peptic ulcer who underwent repeated elective follow-up endoscopies with
biopsies within 1 year. Glaucoma parameters were prospectively recorded at
baseline and after 1 and 2 years of follow-up with the same topical medication
regimen. The ophthalmologists treating the patients in this study were masked
to the H pylori status of these patients.
The follow-up study population was classified into 3 glaucoma groups:
patients for whom H pylori treatment was successful
(group A); those for whom eradication of H pylori
had failed (group B); and those who were H pylori
negative at baseline (group C).
STATISTICAL ANALYSIS
The prevalence of H pylori and respective 95%
confidence intervals (CIs) were calculated at 3 months after eradication treatment.
For the patients' age (years), the Mann-Whitney U
test was used, whereas for sex, the Fisher exact test was applied. The latter
test was also used to assess the progress of the various upper GI endoscopic
and histologic findings 3 months after treatment. An unpaired t test was applied to compare the glaucoma parameters of groups A and
B with group C. For all glaucoma parameters (intraocular pressure and visual
field data [CLV, MD, and SF]), comparisons were made between baseline and
after 1 and 2 years of follow-up with the paired t
test and 95% CIs of the difference. The paired t
test was also applied to compare the H pylori serologic
status at baseline with that at 3 months after treatment. Significance was
set at P<.05.
RESULTS
The patients with glaucoma had a higher prevalence of H pylori infection than controls, as verified by the histologically
confirmed presence of H pylori in 36 (88%) of 41
glaucoma cases, including 6 patients who tested negative in the gastric mucosa
urease test, and in 14 (47%) of the 30 control subjects ( 2
= 14.075, P<.001; Table 1). The odds ratio for the association of H pylori with OAG was 8.23 (95% CI, 2.35-28.83). The mean serum IgG
anti–H pylori level was also significantly
higher in patients with glaucoma (35.6 ± 31.1 U/mL) than in controls
(17.03 ± 18.1 U/mL; P = .002). In patients
with glaucoma and controls, the diagnosis of esophagitis, gastritis, duodenitis,
and/or peptic ulcer was made during endoscopy and confirmed histologically
(Table 2).
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Table 1. Helicobacter pylori Positivity in
Patients With Glaucoma and Controls*
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Table 2. Endoscopic and Histologic Characteristics of the 3 Groups
of Glaucoma Patients at Baseline and 3 Months After Treatment*
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OUTCOME OF H PYLORI ERADICATION THERAPY
Helicobacter pylori eradication therapy was
successful in 30 (83%) of the 36 patients who were positive for H pylori at baseline (group A). Treatment was unsuccessful in the remaining
6 patients (group B). All patients were compliant with their therapy as determined
by the number of tablets and capsules remaining after therapy. Adverse effects
were generally mild and included mild abdominal pain, occasional nausea or
vomiting, diarrhea, stomatitis, and headache. None of the patients discontinued
their therapy because of these mild adverse effects.
When compared with baseline values (42.6 ± 31.0 U/mL), the mean
serum IgG anti–H pylori level was significantly
reduced in group A patients at 3-month follow-up (19.6 ± 14.3 U/mL)
(P<.001). In group B patients, this parameter
had increased at 3-month follow-up (28.5 ± 21.6 U/mL at 3 months vs
25.4 ± 19.4 U/mL baseline; P = .04). In group
C patients, who did not receive H pylori eradication
therapy, both mean serum IgG anti–H pylori
values were below positive-limit levels (7.2 ± 1.6 U/mL at 3 months
vs 6.0 ± 1.9 U/mL at baseline; P = .03).
All 5 group A patients with ulcers (2 duodenal and 3 gastric) were endoscopically
confirmed to have healed at 3-month follow-up (P
= .03; Table 2). In group B, endoscopic
parameters and chronic gastritis activity did not show statistical differences
between baseline readings and the values at 3 months, although ulcer healing
did occur in 2 duodenal ulcers in this group. All 5 patients in group A with
peptic ulcer disease who were reexamined 1 year after undergoing the eradication
regimen remained free of the infection.
At baseline, comparisons for endoscopic evidence of esophagitis and
duodenitis did not reveal significant differences between patients with glaucoma
and controls. Patients with glaucoma more often than controls exhibited histologically
confirmed antral gastritis (38/41 vs 17/30; P<.001)
and peptic ulcer disease (7/41 vs 0/30; P = .01).
OUTCOME OF GLAUCOMA PARAMETERS
Baseline visual field indices including MD and CLV were significantly
lower in group C than in groups A and B (P = .04
for both), whereas no significant difference was observed in short-term fluctuation
between these groups. Table 3
and Figure 1, Figure 2, Figure 3, and Figure 4 detail and illustrate the glaucoma
parameters in all glaucomatous eyes (n = 74) of the 41 patients at baseline
and 1 and 2 years after treatment. At the treatment end points selected in
the present study (1 and 2 years), a significant improvement was found for
all glaucoma parameters in group A compared with baseline readings except
for MD at 1 year, the change for which did not reach statistical significance
(P = .25). In contrast, glaucoma parameters did not
differ or slightly deteriorated statistically from baseline to 1- and 2-year
follow-up values in groups B and C.
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Table 3. Comparison of Mean Intraocular Pressure and Visual Field Parameters
for All Glaucoma Cases at Baseline and After 1 and 2 Years of Follow-up*
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Figure 1. Mean intraocular pressure at baseline
and 1 and 2 years after treatment in patients for whom Helicobacter
pylori treatment was successful (group A); those for whom eradication
of H pylori had failed (group B); and those who were H
pylori negative at baseline (group C). Error bars indicate SD.
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Figure 2. Mean short-term fluctuation at
baseline and 1 and 2 years after treatment in patients for whom Helicobacter
pylori treatment was successful (group A); those for whom eradication
of H pylori had failed (group B); and those who were H
pylori negative at baseline (group C). Error bars indicate SD.
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Figure 3. Mean corrected loss variance at
baseline and 1 and 2 years after treatment in patients for whom Helicobacter
pylori treatment was successful (group A); those for whom eradication
of H pylori had failed (group B); and those who were H
pylori negative at baseline (group C). Error bars indicate SD.
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Figure 4. Mean defect values at baseline
and 1 and 2 years after treatment in patients for whom Helicobacter
pylori treatment was successful (group A); those for whom eradication
of H pylori had failed (group B); and those who were H
pylori negative at baseline (group C). Error bars indicate SD.
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COMMENT
Glaucomas comprise a group of age-related eye diseases that share common
clinical and morphological features. These include an intraocular pressure
too high for the health of the eye; progressive, insidious damage to the optic
nerve; and visual field loss. It is estimated that more than 3 million Americans
and more than 67 million people worldwide have glaucoma. Thus, glaucoma is
currently the second leading cause of blindness in the Western world.1, 4
Much remains to be learned about glaucoma, not only at the level of
pathogenesis but also with regard to its systemic associations and influences.
Among the key events in glaucoma are increased outflow resistance at the level
of the trabecular meshwork, increased intraocular pressure, and a characteristic
optic neuropathy. The only way to prevent visual loss with glaucoma is early
diagnosis and treatment. At the present time, glaucoma therapy entails decreasing
aqueous humor production, increasing fluid drainage, or a combination of these
2 using medical, laser, or surgical means.4
This approach, however, treats only a risk factor (elevated intraocular pressure)
and not the disease per se and thus fails to address the events that lead
to the elevated intraocular pressure. A far more rational management of glaucoma
in the future may be to direct our therapeutic interventions to the risk factors
leading to glaucomatous neuropathy.4 However,
appropriate management of glaucoma requires a better understanding of the
pathogenetic mechanisms involved.
As knowledge of glaucoma has accumulated, ophthalmologists have increasingly
focused on prevention of the initial events that lead to optic nerve damage.
Important to determining who will contract glaucoma are a number of risk factors,
of which raised intraocular pressure is the best known. Several of these risk
factors, such as advancing age and family history, are not modifiable. However,
other risk factors may be modifiable, and their elimination may help to decrease
incidence of blindness from glaucoma. Significantly, the populations of patients
with glaucoma have a higher prevalence of systemic conditions such as arterial
hypertension, obesity, and diabetes. To date, the increased prevalence of
glaucoma in patients with these conditions has not been elucidated. Consequently,
when the ophthalmologist treats glaucoma, he or she is treating a patient
more likely to have, or be at greater risk for developing, vascular disorders.
In addition, the most widely prescribed medicine to treat glaucoma (timolol,
a topical  -blocker) may adversely affect serum lipid levels.16 Thus, understanding how systemic disorders adversely
affect glaucoma risk, as well as the effect of treatment of systemic conditions
on glaucoma course and prognosis, may lead to better overall care of the patient
with glaucoma.
In the first part of this study, by documenting a higher prevalence
of H pylori in an OAG cohort than in an age- and
sex-matched control group, we established for the first time a significant
relationship between H pylori infection and glaucoma
in a Greek ethnic cohort.12 The H pylori infection was determined by histologic detection of organisms
in mucosal biopsy specimens, which is considered the gold standard for the
diagnosis of this infection. The H pylori prevalence
of our control group is similar to that reported by other investigators who
used serodiagnostic assay to evaluate Greek cohorts and other ethnic populations
(frequency distribution, 34.1%-61.6%).6
It is worthwhile to consider whether the rate of H pylori infection in the control group has been negatively influenced
by the coexistence of anemia. There is no evidence to suggest that anemia
protects against development of H pylori infection.
Anemic controls have been used before,17 and
the frequency of H pylori infection in the anemic
control group matches that of the general population in Greece and that reported
in other ethnic groups.6 Furthermore, it is
unlikely that individuals with iron-deficiency anemia are protected against H pylori infection because it is thought that the infection
is actually associated with iron- and/or vitamin B12–deficiency
anemia.18-19 In addition, eradication
of H pylori infection may be associated with reversal
of iron and/or vitamin B12 deficiency and improvement of anemia.20
In part 2 of the present study, we obtained an acceptable eradication
rate of 83% by using a triple eradication regimen of omeprazole, clarithromycin,
and amoxicillin for 1 week, which is standard practice in Europe. Similar
eradication rates have been achieved by others.5
Moreover, recurrence of duodenal and gastric ulcers was prevented after a
successful H pylori eradication regimen for up to
1 year, findings that have also been reported for long-term follow-up periods.21
The present study established that patients in whom H pylori was successfully eradicated (group A) showed a statistically
significant reduction in intraocular pressure at both clinical end points
(1 and 2 years after treatment). This was not the case in groups B and C,
despite the fact that all groups were maintained on the same antiglaucoma
therapy they received at baseline. Thus, it seems that H pylori eradication was beneficial for the intraocular pressure control
in these patients. Although a reduction of 1.2 mm Hg may not seem clinically
significant (as opposed to statistically significant), we should bear in mind
the progressive nature of glaucoma and the fact that all patients were maintained
on the same regimen for 2 years. Longer-term follow-up is required to validate
the beneficial effect of H pylori eradication therapy.
Results of the present study suggest that eradication therapy may somehow
improve the outflow facility of the eye. It should be noted, however, that
the numbers of patients in groups B and C were small, and it may not, therefore,
be possible to draw definitive conclusions. Future studies are needed to focus
on the influence of H pylori in the outflow system
of the eye. It is conceivable that H pylori induces
the synthesis of various mediators (eg, cytokines), which may be detrimental
to the outflow system of the glaucomatous eye. A fruitful line of future investigation
would be comparison of the aqueous humor of patients with glaucoma who test
positive for H pylori with those who test negative
for the infection.
A similar improvement occurred in visual field data (mean SF and CLV
at 1 and 2 years' follow-up). These results in group A are of interest because
it is unusual for these parameters to improve over time. It should be noted
that these changes occurred while patients were maintained on the same glaucoma
regimen. Group B patients, on the other hand, showed a slight deterioration
in SF and CLV mean values after 2 years of follow-up. These findings clearly
suggest that patients in group A did better than those in group B over a period
of 2 years. It is reasonable to hypothesize that it was the H pylori eradication that improved the parameters of these patients.
These results are encouraging and suggest that possibly H pylori eradication should be attempted in patients with glaucoma.
However, before this strategy becomes established practice, further evidence
from large-scale prospective trials in various ethnic groups is needed to
confirm our findings.
With regard to group C patients (H pylori negative
at baseline), it is interesting to note that all baseline visual field indices
were approximately within upper normal limit values and, in particular, 2
baseline visual field indices (MD and CLV) were significantly lower than in
groups A and B. In addition, all glaucoma parameters showed a slight worsening
over time, although these changes were not statistically significant. We do
not know whether these observations will persist or progress over a longer
period of follow-up. Because of the small number of glaucoma cases included
in this group, future studies are needed to elucidate the natural course of H pylori–negative patients.
It should be noted that local administration of antiglaucoma drops results
in systemic absorption through the nasal mucosa. It is known, for example,
that within the upper GI tract, prostaglandins seem to heal ulcers by secretory
inhibition rather than "cytoprotective" actions.22
Therefore it is conceivable that latanoprost treatment (a prostaglandin analogue)
may have influenced slightly the alimentary tract by inducing minor ulcer
healing activity via inhibition of acid secretion. Timolol, a nonselective -adrenoreceptor
antagonist, is known to have failed to protect against ethanol-induced gastric
lesions23 and is not believed to meaningfully
affect the GI tract. Pilocarpine has been known to affect GI motility, and
potential effects on the GI tract include prolonged salivary secretion, diarrhea,
and acid secretion.24-25 Swallowed
saliva secretion induced by pilocarpine might neutralize, at least in part,
acid output. However, only 1 patient received pilocarpine in our group.12 We think that it is the administration of omeprazole
(strong proton pump inhibitor under all known stimuli)22
that was the major contributor to ulcer healing in H pylori–positive and H pylori–negative
patients.
The question arises exactly how H pylori infection
influences the pathophysiology of glaucoma. The following possible mechanisms
are suggested. Helicobacter pylori may promote the
formation of L- and P-selectin–dependent platelet-leukocyte aggregates
in murine gastric microvessels, and H pylori may
also induce platelet activation and aggregation26-27
and atherosclerosis.9 This phenomenon may play
a part in the proposed relationship between H pylori
and glaucoma, in which platelet activation and aggregation play a relevant
pathophysiological role.28-29
Alternatively, release of large amounts of variable proinflammatory and vasoactive
substances such as cytokines (interleukin [IL] 1, IL-6, IL-8, IL-10, IL-12,
tumor necrosis factor  , and interferon  ), eicosanoids (leukotrienes
and prostaglandins), and acute-phase proteins (fibrinogen and C-reactive protein)
following gastric colonization by H pylori10, 30-31 may be involved in
a number of vascular disorders thought to be associated with the bacterium.
These disorders include Raynaud phenomenon, idiopathic migraine, coronary
heart disease,10, 30-31
and now possibly glaucoma (a similar cytokine profile seems to be involved
in the pathogenesis of glaucoma disease).32-33
Increased endothelin-1 (a potent constrictor of arterioles and venules), nitric
oxide, and inducible nitric oxide synthase levels in peptic ulcer disease
associated with H pylori infection34
suggest that the resulting microcirculatory disturbance may be a major factor
in the pathogenesis of local gastric mucosal ulceration and systemic damage,
including glaucoma. Indeed, endothelin-1–induced vasoconstriction of
the anterior optic nerve vessel and modulation of vascular tone in the ophthalmic
artery by nitric oxide may be involved in the pathogenesis of glaucomatous
damage.3, 35 Helicobacter pylori can coagulate blood by stimulating mononuclear
cells. Under bacterial stimulation, mononuclear leukocytes produce a tissue
factor–like procoagulant activity that, through the extrinsic pathway
of blood coagulation, converts fibrinogen into fibrin. Thus, apart from its
effect on fibrinogen level, H pylori has another
activity (blood clotting), which might contribute to the pathogenesis of cardiovascular
disorders36 or glaucoma. Other factors such
as the development of cross mimicry between endothelial and H pylori antigens10 and excessive production
of reactive oxygen metabolites and circulating lipid peroxides, which are
associated with cardiovascular risk in patients with H pylori infection,7, 36 may also
be involved indirectly in glaucoma pathophysiology. However, further studies
are needed to elucidate these points.
AUTHOR INFORMATION
Accepted for publication October 2, 2001.
Corresponding author and reprints: Jannis Kountouras, MD, PhD, 8
Fanariou St, Byzantio, Thessaloniki 551 33, Thessaloniki, Macedonia, Greece
(e-mail: jannis{at}med.auth.gr).
From the Departments of Medicine, Second Medical Clinic, Aristotle
University of Thessaloniki (Drs Kountouras, Chatzopoulos, Zavos, and Boura),
Ophthalmology (Dr Mylopoulos), and Pathology (Dr Venizelos), Ippokration Hospital,
and the University Department of Ophthalmology, AHEPA Hospital (Dr Konstas),
Thessaloniki, Greece.
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