GASTROENTEROLOGY 2000;118:795–801

EDITORIALS

The Efficacy and Safety of Long-term Omeprazole Treatment

for Gastroesophageal Reflux Disease

tients do not differ with respect to the required mainte-

See article on page 661.
nance dose or the number of relapses. This is in
agreement with other data in GERD patients, which have
n the past 15 years, proton pump inhibitors (PPIs)
I have led to considerable change in the treatment of
acid-related disorders, especially gastroesophageal reflux
shown no relation between H. pylori and either the
required PPI maintenance dose,6 24-hour esophageal acid
exposure,7,8 or relapse frequency during PPI use.9 In
disease (GERD). Their ability to suppress acid without contrast, a meta-analysis of 3 studies on the efficacy of
significant development of tolerance or side effects has led omeprazole, ranitidine, or placebo for GERD demon-
to widespread use. In the Netherlands and the United strated that the healing of esophagitis and relief of
Kingdom, 1%–2% of the population is estimated to use heartburn did not depend on H. pylori, but its presence
PPIs at least 3 months per year. Maintenance PPI therapy did prevent against disease relapse during treatment.10
has been studied in a few long-term cohorts, including 2 Because Klinkenberg-Knol et al.4 defined relapse as
from Germany1,2 and 1 multinational from Australia, endoscopic grade II or more severe esophagitis, the actual
Canada, the Netherlands, and Sweden.3 The latter study, number of clinical relapses must have been somewhat
in which patients with H2-blocker resistant GERD were higher than reported. If a relapse occurred, the protocol
treated from 1985 onwards, had the largest follow-up required a stepwise increase of omeprazole. Thus, some
with annual endoscopies and biopsy sampling. The study patients were eventually treated with 80–120 mg omepra-
was recently terminated after a mean 6.5 years’ follow-up zole daily divided into 2 doses. In a subset of patients
and gradual withdrawal of 52% of the original study from the same protocol, the investigators previously
population. In this issue of GASTROENTEROLOGY, the showed that acid breakthrough occurred particularly
international group of investigators present the final during the night.11 The addition of an H2-blocker before
results of their study with respect to efficacy and safety of bedtime might have prevented this nocturnal break-
omeprazole maintenance treatment for GERD.4 through and the need for a further increase of omeprazole
in some patients.12 The omeprazole maintenance data
The Efficacy of Omeprazole also show that the results of PPI treatment are at least as
for GERD good as those of antireflux surgery. The higher complica-
In the study of Klinkenberg-Knol et al.4 86% of tion rate and the more than occasional need to undergo
patients with severe erosive esophagitis healed within 12 surgery again have limited the revival of fundoplication
weeks of using 40 mg omeprazole. These data confirm the despite the introduction of laparoscopic techniques.
efficacy of this drug. The authors provide information on Endoscopic techniques such as tightening of the gastro-
whether healing rates depended on Helicobacter pylori. In a esophageal junction by endoscopic suturing or local
recent clinical trial, H. pylori–positive GERD patients submucosal electrocoagulation are now being studied for
responded significantly better to 40 mg pantoprazole their efficacy and safety. The results of those studies will
once daily than H. pylori–negative patients.5 The differ- have to be compared with the current gold standard of
ence in endoscopic healing rates was 10% after 4 weeks PPI treatment, as well as antireflux surgery.
and 4.6% after 8 weeks of treatment. Heartburn and Despite the low number of GERD relapses, PPI
regurgitation also improved significantly more in H. maintenance therapy does not prevent the development
pylori–positive patients after 4 weeks, but this difference of Barrett’s esophagus. Klinkenberg-Knol et al.4 observed
was no longer present after 8 weeks. H. pylori augments that 20 of 166 (12%) patients without Barrett’s metapla-
the effect of PPIs on intragastric pH, probably caused by sia at baseline developed this condition during follow-up.
a combination of factors including urease activity and the Because the natural incidence of Barrett’s esophagus in
induction of corpus gastritis impairing parietal cell GERD patients is unknown, it is unclear whether this
function. However, this effect is limited, and the present number of new cases differed from expected. The effect of
study shows that H. pylori–positive and –negative pa- omeprazole maintenance therapy on preexisting Barrett’s
796 EDITORIALS GASTROENTEROLOGY Vol. 118, No. 4

mucosa is also still a matter of debate. In the present data.18–21 In both the Lundell study17 and the present
study, no progression or regression of preexisting Bar- study, atrophic gastritis was usually preceded by moderate-
rett’s mucosa was observed in any patient. In contrast, 2 to-severe corpus gastritis, but the prevalence of such
randomized trials reported some regression during treat- inflammation at baseline among H. pylori–positive pa-
ment with 40 mg omeprazole twice daily,13,14 whereas a tients was much higher in the Lundell cohort, possibly
third study reported no regression after administration of caused by pretreatment with omeprazole.
20 mg omeprazole once daily.15 Thus, it seems that if PPI Unlike the studies mentioned previously, one cross-
treatment induces any regression of Barrett’s metaplasia, sectional study observed a similar prevalence of atrophy
this only occurs during high-dose treatment with com- among omeprazole-treated GERD patients and dyspeptic
plete prevention of esophageal acid exposure. controls.21 However, cases and controls differed with
respect to underlying disease, and baseline histology was
The Safety of Omeprazole for GERD lacking precluding conclusions about the rate of develop-
ment of atrophy. In a study of another PPI, lansoprazole,
The study by Klinkenberg-Knol et al.4 further the incidence of atrophy in H. pylori–infected subjects
supports the long-term safety of omeprazole treatment. was consistent with the observations during omeprazole
After almost 1500 patient-years of follow-up, no serious therapy.22
adverse events were related to this drug. The only effects The issue of H. pylori, acid, and gastritis has been
related to omeprazole were those observed in the gastric debated extensively in the past 4 years. Scoring of
mucosa. Most importantly, this study confirms that atrophic gastritis may be biased by the presence of
omeprazole does not cause inflammation, atrophy, or inflammation, and the increase of corpus inflammation
argyrophil cell hyperplasia in H. pylori–negative patients. associated with PPI use in H. pylori–positive subjects may
However, in H. pylori–positive patients, omeprazole
give a false impression of gland loss.23 Although this
treatment was associated with a worsening of corpus
issue may cause difficulty in some cases, it seems unlikely
gastritis, as reported previously.16 The prevalence of
that systemic errors are made by experienced pathologists
inflammation, already more than 80% at baseline, re-
who do not rely on the distribution of glands alone to
mained unchanged. The increased severity of body gastri-
identify gland loss, but consider the presence of fibrosis or
tis facilitated the development of atrophy; 30 of 32 (94%)
metaplasia as a prerequisite for atrophy. We recently
patients who developed corpus atrophy during follow-up
measured the volumes of gland epithelium, infiltrate, and
had moderate-to-severe body gastritis. The annual inci-
dence of corpus atrophy, 0.7% in H. pylori–negative and stroma in histological slides.24 Atrophy scores given by 2
4.7% in H. pylori–positive patients, was also in agree- experienced pathologists using the updated Sydney sys-
ment with previous observations.16 These observations tem closely correlated with the measured volumes of
support the concept that progression to gland loss is very specialized epithelium. Increasing grades of atrophy
slow in the absence of H. pylori gastritis, irrespective of correlated better with a 4-fold greater decrease in epithe-
acid output. However, in the presence of H. pylori, PPI lial volume than the accompanying increase in infiltrate
use is invariably associated with increased H. pylori– volume. Increasing grades of atrophy correspond to a true
induced corpus inflammation, which accelerates the loss of epithelial volume instead of a surrogate loss caused
progression to gland loss. Various prospective studies by an increase of infiltrate. Moreover, one observes a
have shown that approximately 1%–3% of H. pylori– gradual decrease of serum vitamin B12 levels in H.
positive patients develop atrophic gastritis annually. pylori–positive patients who develop moderate to severe
After vagotomy, or during PPI therapy, progression to corpus atrophy during PPI use.25 Atrophy development
gland loss occurrs at a rate of 4%–8% annually,16 similar is mostly preceded by moderate-to-severe inflammation,
to the data presented in this issue. In a recent multicenter but the exact mechanisms leading to gland loss are still
Scandinavian study, progression to atrophic gastritis did unclear. In a recent elegant animal study, Wang et al.26
not significantly differ after fundoplication or during suggested that gland loss may directly result from
omeprazole therapy.17 Unfortunately, the study had sev- hypergastrinemia. Transgenic mice with moderate hyper-
eral flaws including insufficient size and power to reach gastrinemia showed progression to atrophic gastritis and
significance at the expected difference between both gastric cancer even in the absence of chronic gastritis, a
groups.18 Moderate-to-severe atrophic gastritis was ob- process accelerated by colonization with H. felis. The
served at a rate of 1.5% annually in the fundoplication authors hypothesized that increased gastrin levels up-
group and 6.0% in the omeprazole group, which, despite regulate growth factors such as transforming growth
the lack of significance, is consistent with previous factor ␣, which would then play a role in the develop-
April 2000 EDITORIALS 797

ment of foveolar hyperplasia and loss of parietal cells and sion on H. pylori gastritis and progression to atrophic
gastric glands. gastritis have clinical consequences. Intervention by H.
Not only the exact mechanisms but also the conse- pylori eradication during PPI use eliminates gastric
quences of gland loss in H. pylori–positive GERD mucosal inflammation,35 but longer follow-up is needed
patients during PPI treatment are still unclear. Apart to show that this can prevent gland loss. Also, for a better
from the potential long-term effects on vitamin B12 understanding of the mechanisms underlying the forma-
levels, loss of gastric glands with specialized cells may tion of atrophy and metaplasia, the molecular abnormali-
actually be beneficial for reflux disease itself, because a ties that almost certainly govern this complex dynamic
reduction of acid output may facilitate GERD treatment. process need to be explored.
Concerns focus on the potentially increased risk for
gastric cancer. It seems reassuring that few patients ERNST J. KUIPERS
develop intestinal metaplasia during the first years of PPI STEPHAN G. M. MEUWISSEN
treatment, which is always type I metaplasia.4,17,23 How- Department of Gastroenterology
ever, the follow-up after development of gland loss in all Free University Hospital
these studies is only a few years. The natural progression Amsterdam, the Netherlands
to atrophy and subsequent metaplasia takes much longer,
and it thus remains unclear whether gland loss in H. References
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quantitative assessment of gastric corpus atrophy in tissue Address requests for reprints to: Ernst J. Kuipers, M.D., Ph.D.,
sections (abstr). Gastroenterology 2000;118:(in press). Department of Gastroenterology, Free University Hospital, P.O. Box
25. Schenk BE, Kuipers EJ, Klinkenberg-Knol EC, Sandell M, Nelis GF, 7057, 1007 MB Amsterdam, the Netherlands. e-mail: kuipers@
Snel P, Festen HPM, Meuwissen SGM. Atrophic gastritis during azvu.nl; fax: (31) 20 444 0554.
long-term omeprazole therapy affects serum vitamin B12 levels. r 2000 by the American Gastroenterological Association
Aliment Pharmacol Ther 1999;13:1343–1346. 0016-5085/00/$10.00
26. Wang TC, Dangler CA, Chen D, Goldenring JR, Koh T, Ray- doi:10.1053/gg.2000.6556

Maintaining Gut Homeostasis: The Butyrate–NF-␬B Connection

of atrophy, the drug will exert trophic effects, whereas if

See article on page 724. there is too much growth, as in neoplasia, the drug will
cause cell cycle arrest and apoptosis. Finally, the ideal
et us imagine the ideal drug for the gut epithelium,
L one that will do whatever is needed to maintain the
delicate balance among growth, differentiation, apopto-
drug will prevent excess inflammation, e.g., in conditions
such as inflammatory bowel disease. Is it possible that
such an ideal substance already exists in the four-carbon,
sis, and ‘‘physiological’’ inflammation. Under conditions short-chain fatty acid butyrate?