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Pankaj
Singh, Anant Indaram, Ronald Greenberg, Vernu Visvalingam and
Simmy Bank Division
of Gastroenterology, Albert Einstein Colege of Medicine, Long Island
Jewish Medical Center, New Hyde Park, New York
Dr. Pankaj Singh is a second year gastroenterology fellow in Albert
Eins tein College of Medicine, Long Island Jewish Hospital. He did
his residency in medicine from King George Medical College, India
and then from State University of New York, NY. He is currently
studying the effect of alcohol on apoptosis in pancreatic cells.
Correspondence to: Dr. Pankaj Singh, Department of
Gastroenterology, Long Island Jewish Medical Center, 270-05 76th
Ave, New Hyde Park, NY 11040, USA
Telephone:
(718)-347-2393
Received: 2000-10-13 Accepted: 2000-10-22
Subject
heading: gastroesophageal reflux;
proton pump inhibitors; enterochromaffin cell; hypergastrinemia;
carcinoid tumor; biopsy
Long term omeprazole therapy for reflux esophagitis: follow-up in
serum gastrin levels, EC cell hyperplasia and neoplasia.
World J Gastroentero, 2000;6(6):789-792
Abstract
AIM: To evaluate the long-term
safety of omeprazole in patients of gastroesophageal reflux disease
resistant to treatment with H2 receptor antagonist.
METHODS: We prospectively followed 33 patients on omeprazole
therapy for severe erosive esophagitis for 5-8 years, with periodic
gastrin levels, H. pylori infection, gastric biopsies for
incidence of ECL cell hyperplasia, carcinoids, gastric atrophy and
neoplasia. A total 185 patient follow-up years and 137 gastric
biopsies were done.
RESULTS: Among the 33 patients, 36% reached their peak
gastrin levels in an average of 8 months to one year, then drifted
Down slowly over 1-2 year period to just above their baseline level,
24% of the patients had a peak gastrin level above 400ng·L-1
and one patient had a peak level above 1000ng·L-1.
One patient had a mild ECL cell hyperplasia which was self limiting
and did not show any dysplastic changes. Eighteen percent of
patients were positive for H. pylori infection. The gastric
biopsies did not show gastric atrophy, intestinal metaplasia or
neoplastic changes.
CONCLUSION: In a series of 33 patients followed for 5-8 years
on omeprazole therapy for severe reflux esophagitis, we did not
observe any evidence of significant ECL cell hyperplasia, gastric
atrophy, intestinal metaplasia, dysplasia or neoplastic changes.
INTRODUCTION
Acid suppression therapy plays a pivotal role in the medical
management of reflu x esophagitis. The most recently developed acid
suppressive agents, the proton pump inhibitors (PPIs) directly
inhibit hydrogen ion exchange and inhibit acid secretion in response
to all stimulatory agents[1-5]. The PPIs are
benzimidazole derivatives, which are converted to active metabolites
within the acidic confines of the secretary canaliculi of the
gastric parietal cells. They promote oxidation of sulphydryl
components of the proton pump, leading to irreve rsible inactivation
of the enzyme[1]. Recovery of acid secretion requi res
synthesis of new proton pumps. There is now a definite evidence that
PPIs are more effective than H-2 receptor antagonists in treating
esophagitis, seve re refractory reflux disease and non-healing
esophageal ulcers, providing fast er healing and symptomatic relief[6-9].
Esophagitis is however a chroni c problem,as early relapses have
been observed after cessation of H-2 blockers and omeprazole[7,8].Therefore,
maintenance treatment is often required in treating the reflux
esophagitis. H-2 blocker has failed, as an effective maintenance
agent in preventing the relapses[9,10]. There is enough
evidence to support the role of PPIs as an effective ag ent in
maintaining healing of erosive esophagitis[8,11-16].
However, questions regarding the long-term safety of the proton pump
inhibitors have bee n raised. The resulting hypo-/achlorhydria and
resulting hypergastrinemia have been implicated in the development
of enterochromaffin cell hyperplasia and gastric carcinoids[17-20].
The epidemiological evidence of increased incidence of gastric
fundal carcinoma has further raised concerns regarding, gastric
atrophy and the long term use of PPIs in acid related peptic
diseases , especially in patients with H. pylori infection[21].Considering
the efficacy of PPIs and possibility of their role in developm ent
of EC cell hyperplasia, it was logical to study their safety profile
as long term maintenance therapeutic agents in esophagitis.
MATERIALS AND METHODS
At Gastroenterology Department, Long Island Jewish Medical
Center 33 patients with severe reflux esophagitis of grade 2 and
above, whose symptoms were not res ponding to H2 blockers and
motility agents were enrolled in the study. Patient s were started
on omeprazole (PPI) either daily or on an alternate day regimen and
were followed periodically for symptom relief, endoscopic healing,
plasma gastrin level, H. pylori infection and gastric
biopsies for occurrence of neoplasia. Esophagitis was graded
endoscopically using the following scale: grade 0, normal appearing;
grade 1, mucosal edema, hyperemia and/or friability; grade 2, one or
more erosions/?ulcerations involving ＜10%
of the distal five cm of the esophagus; grade 3, erosions/?ulceration＇s
involving 10% to 50% of the distal 5cm of the esophagus or an ulcer
3mm-5mm in diameter. In cases of Barrett＇s
esophagus, the area 5cm proximal to the squamo-columnar junction was
evaluated; grade 4, multiple erosions involving 50% of the distal
5cm of the esophagus or a single ulce r ＞5mm
in diameter. Whenever clinically feasible, all endoscopies for a
particular patient were performed by the same endoscopist. Complete
healing of erosive reflux esophagitis was defined as the return of
esophageal mucosal inflammation to grade 0 or grade 1.
Periodic
plasma gastrin levels were measured after an 8 hours fast prior to
endo scopy. Four gastric biopsy specimens of full thickness of the
mucosa (two fundal, two antrum) were obtained at the screening visit
and at the end of 8-12 weeks to assess healing. At intervals of 6 to
12 months periodic upper endoscop ies were performed to monitor for
carcinoids, gastric atrophy and gastric neopla sia. Bouin＇s
fixed, paraffin-embedded, 3 microns hematoxylin and eosin-stained
sections of each biopsy specimen were evaluated and graded for
active and chronic inflammation. The presence of intestinal
metaplasia, atrophy, dysplasia and neoplasia was evaluated. The
enterochromaffin like cells of the oxyntic gastric mucosa were
assessed using Grimelius stain sections and Solcia＇s
scale of gastric endocrine growth. Two independent pathologists who
were blinded to each other＇s
assessments of the biopsy specimens reviewed gastr ic biopsies.
H.
pylori infection was assessed by identifying the organisms and
chronic inflammation in the biopsy specimens, serum H. pylori
IgG antibodies or by CLO test. Out of the 33 patients, 22(66%) were
male and 11(34%) were female (Table 1). The mean age of the patients
was 76 years with a range of 34 to 86 years (Figure 1). Twenty-six
(78%) patients were on omeprazole daily 10mg-20mg or 10mg-20mg twice
daily. Seven (21%) patients were on alternate day 10mg-20mg
omeprazole therapy for severe reflux esophagi tis (Table 1).The
average period of follow-up was for 6 years, with a range of 3 to 8
years, a total of 185 patient years of follow up (Figure 2). The
total number of biopsies done was 137, averaging 4, with a range of
2 to 13.
Table 1 Type of treatment and sex distribution (n=33)
|
Group
|
Number
|
|
Alternate
day omeprazole therapy
|
7
|
|
Daily
omeprazole therapy
|
26
|
|
Male
patients
|
22
|
|
Female
patients
|
11
|
RESULTS
Twelve (36%) of the patients reached
their peak plasma gastrin levels in one year, and then drifted to a
level above their baseline levels in 1 to 2 years. Three (9%)
reached their peak in 2 years, 5 (15%) in 3 years, 3(9%) in 4 years,
5 (15%) in 5 years, 2 (6%) in 7 years, 1 (3%) in 8 years (Figure 3).
Eleven (33%) of patients had plasma gastrin levels below 100pmol·L-1,
24% of patients above 400pmol·L-1
and in one patient it was above 1000 pmol·L-1.
Gastric biopsies showed normal mucosa on initial biopsy in 26 and
gastritis in 7. On repeat biopsy 7 changed from normal to gastritis
and 4 from gastritis to normal. Nineteen were normal at all times.
Of the 6 Hp+ (H. pylori positive) patients, 1 was normal on all
occasions, 2 showed gastritis, 2 varied from normal to gastritis and
1 from gastritis to normal. Of the 27 Hp negative patients, 18 were
normal at all times, 1 showed gastritis, 5 varied from normal to
mild gastritis and 3 from gastritis to normal . No atrophy was
diagnosed at any time over the 5-8 years, on any of the 137 biopsy
specimens.
EC
cell hyperplasia was seen in one of the biopsies. Neither fundal
gastric neoplasia, nor carcinoids were seen(Table 2).
Table 2 Results of gastric biopsies in-patients on long term
omeprazole therapy for reflux esophagitis
|
Pathology
|
Number
|
|
Normal
throughout the treatment
|
19
|
|
Normal
at onset, later gastritis changes
|
7
|
|
Initial
fundal gastritis
|
7
|
|
Initial
gastritis changed to normal
|
4
|
|
ECL
cell hyperplasia
|
1
|
|
Barretts
esophagus
|
4
|
|
H.
pylori infection +ve
|
6
|
|
H.
pylori infection -ve
|
27
|
Figure
1(PDF) Age distribution of
patients on long-term omeprazole treatment for reflux esophagitis.
Figure 2(PDF)
Distribution of follow-up years of patient s on long-term
omeprazole treatment for reflux esophagitis.
Figure 3(PDF)
Time to reach maximium plasma gastrin levels in patients treated
with long term omeprazole.
DISCUSSION
Esophagitis is a chronic problem with frequent early relapses[7,8].
Therefore, it is not only important to treat the reflux disease but
also to prevent relapses. It is now known that PPIs are more
effective than H-2 receptor antagonist in treating refractory reflux
disease[1,6,12-16]providing faster healing and
symptomatic and in preventing early relapses[9,10].
Concerns were raised regarding the safety of PPI as a long-term
maintenance agent[17-19]. In our study, we found
omeprazole to be a safe drug even when used over a long period.
Hypochlorhydria, encountered with PPIs has strong association with
hypergastrinemia[28]. Hypochlorhydria leads to fall in
the secretion of somatostatin from antral D cells. Somatostatin is a
major negative feedback mediator of gastrin release and its absence
leads to persistent gastrin release[22-25]. Because PPI＇s
are better inhibitors of gastric acid secretion than H-2 receptor
antagonist is, they are associated with higher gastrin levels.
Freston et al and other studies showed that plasma gastrin
levels generally peak in the first four months of treatment with
PPIs and stabilize without further increase thereafter[26, 27].
In our studies, the gastrin level peaked on an average in initial
8-12 months of treatment. The early peak in other studies could have
been because of development of gastric atrophy in some of their
patients[26,27]. The same reason was postulated for the
eventual decline in gastrin level. Althou gh we also observed the
decline in gastrin level after a period of 1-2 years, but we did not
observe gastric atrophy in any of our patients. It is not yet clear
why after some time the gastrin levels came down. The consequences
of hypergastrinemia have aroused interest because gastrin has a
trophic effect on gastrin cell, especially ECL cells[26,27].
Rat model studies, have revealed that sustained hypergastrinemia
secondary to PPIs are associated with increased ECL cell hyperplasia
and carcinoid tumor[26-28]. These chang es regress on
bringing back the gastrin level to previously normal levels. In our
study, we did not observe the similar relation between gastrin and
ECL cell hyperplasia and carcinoid. This is in concordance with
other studies done on long term safety profile of PPIs[8,11-16,29].
However, it would be in appropriate to associate similar relations
in humans, given that rats have a higher density of gastrin ECL
cells and a greater gastric response to hypochlorh ydria than humans[21,30].
This is further supported by the fact that, PPIs when used in other
animals (e.g. dogs, guinea pigs, hamsters, mice), do not cause ECL
cell carcinoids.
Borch
et al[31]identified ECL cell carcinoids in
approximately 4% of patients with pernicious anemia, thus raising
the concern that this may be of relevance to use of PPIs. This seems
unlikely as patients who developed carci noid in his study had
gastrin level 10-20 times normal level versus 2-4 folds during
omeprazole treatment. The carcinoids were observed on an average
after a period of 19 years of persistent severe hypergastrinemia[31].The
development of carcinoid has also been observed in patients with
hypergastrinemia secondary to Zollinger Ellison syndrome. All of
these cases had coexisting familial MEN-Ⅰα-syndrome[28].
This combined group of ZES and MEN-Ⅰα-
comprises 25% of all Zollinger Ellison syndromes and the fact that
all the cases of carcinoid has been observed only in this subgroup
suggests that familial factor also plays an important role in
carcinoidogenesis[28]. It would appear from availab le
information that severe and sustained hypergastrinemia is required
to produce ECL cell hyperplasia. When coupled with other factors,
such as genetic trait of MEN-1 syndrome, it may lead to carcinoid
formation.
In
conclusion, our results show that omeprazole is a safe drug, when
used for a long-term maintenance treatment in healing reflux
disease.
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