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Dig Dis Sci (2007) 52:2482–2489
DOI 10.1007/s10620-006-9419-3
REVIEW ARTICLE
Chronic Hypergastrinemia: Causes and Consequences
Lori A. Orlando · Lane Lenard · Roy C. Orlando
Received: 24 April 2006 / Accepted: 30 April 2006 / Published online: 6 April 2007
C
Springer Science+Business Media, Inc. 2007
Abstract The hormone gastrin plays 2 important roles in
gastrointestinal physiology—1 as a major factor in meal-
stimulated gastric acid secretion and the other as a trophic
hormone for epithelial and enterochromaffin cells. These
roles are exaggerated to the point of pathology under con-
ditions of chronic hypergastrinemia as exemplified by the
Zollinger-Ellison syndrome and pernicious anemia. More re-
cently, the concern about the potential risk of chronic hyper-
gastrinemia has risen because of the widespread use of proton
pump inhibitors for maintenance therapy in reflux esophagi-
tis. For this reason, we present a concise overview of the ori-
gin, causes, and potential risks of chronic hypergastrinemia.
Keywords Proton pump inhibitors
.
Hypergastrinemia
.
GERD
Introduction
Hypergastrinemia, by definition, is the presence of serum
gastrin levels above the normal range ( ∼150 pg/mL). Be-
L. A. Orlando
Duke University Center for Clinical Health Policy and Durham
VA, Durham, North Carolina
L. Lenard
DOV Pharmaceutical, Inc.,
Hackensack, New Jersey
R. C. Orlando
Tulane University Health Sciences Center,
New Orleans, Louisiana
L. A. Orlando (
)
Duke Center for Clinical Health Policy and Research,
2200 West Main St, Tower Ste 220, Durham, NC, 27705
e-mail: orlan002@mc.duke.edu
fore the 1970s, chronic hypergastrinemia was an infrequent
occurrence, but when identified, it garnered considerable at-
tention because of its level of elevation ( ∼1000 pg/mL) and
association with Zollinger-Ellison syndrome (ZES) and per-
nicious anemia (PA) [1, 2]. By the late1980s, chronic hyper-
gastrinemia was recognized with increasing frequency due
to its association with gastric infection with Helicobacter py-
lori, and more importantly to the widespread availability of
potent inhibitors of gastric acid secretion with proton pump
inhibitors (PPIs) [3–7]. Unlike what was seen in preceding
decades, PPIs produced a more modest elevation in gastrin
( ∼200–400 pg/mL) and was not associated, in humans, with
any apparent serious pathology [8–11]. Nonetheless, from
their time of release to the present, PPI therapy has evolved
from short-term intermittent treatment to long-term mainte-
nance therapy for gastroesophageal reflux disease (GERD).
Consequently, and as testament to their efficacy, hundreds of
thousands, if not millions, of patients take PPIs, and do so
daily and for periods that stretch from years to a decade or
longer. For this reason, the effect of chronic hypergastrinemia
on human physiology remains of interest. In this manuscript,
we briefly review gastrin’s physiology along with the causes
and potential consequences of chronic hypergastrinemia.
Gastrin physiology
Gastrin is a hormone produced predominantly by G cells
located within the gastric antrum. Its synthesis begins in
the endoplasmic reticulum with the formation of the pro-
hormone, progastrin (Fig. 1). Progastrin is modified in the
golgi apparatus and cleaved in transport vesicles into gas-
trins of varying lengths, namely, gastrin-71, gastrin-34, and
gastrin-17. Prior to being secreted, some gastrins within the
secretory granules are modified into glycine-extended forms
and some undergo amidation (see Fig. 1)[12–15]. Because
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Dig Dis Sci (2007) 52:2482–2489 2483
ER
Progastin Intermediate
Progastrin
Golgi Apparatus
Vesicles
G-71 Gly-G-71
G-34 Gly-G-34
G-17 Gly-G-17
Am G-71
Am G-34
Am -17
Antral G cell
G-71 Gly-G-71
G-34 Gly-G-34
G-17 Gly-G-17
Non-amidated Gastrin Amidated Gastrin
Epithelial proliferation Histamine secretion
Stem Cell differentiation Acid secretion
Secretory Granules
Fig. 1 Gastrin synthesis. ER endoplasmic reticulum, G gastrin, Gly-G
glycine-extended gastrin, Am G amidated gastrin
amidation is influenced by both genetic and environmental
factors, antral G cells vary considerably among individuals in
the types of secreted gastrin. This may be of clinical impor-
tance because amidated and nonamidated forms of gastrin
have different binding affinities for gastrin receptors. There
are 3 types of gastrin receptors: CCK
A
, CCK
B
, and CCK
C
[16]. Amidated gastrins bind to all 3, and notably, are the
only form that binds to CCK
B
receptors on the parietal and
enterochromaffin-like (ECL) cells of the stomach. Conse-
quently, amidated gastrins are the stimulus for gastric acid
secretion. Nonamidated gastrins bind to CCK
A
and CCK
C
receptors. These receptors are progrowth, stimulating epithe-
lia of the digestive tract, especially that of stomach and colon
[17–19]. In addition to the epithelium, CCK
A
receptors are
located on upper intestinal circular smooth muscle so that
amidated and nonamidated gastrins can mediate the relax-
ation of the lower esophageal sphincter, gastric fundus and
sphincter of Oddi [20].
The most prominent action of gastrin is as a driver of
gastric acid secretion. During eating, antral G cells release
gastrin into the circulation in response to gastric antral dis-
tension, pH elevation and contact with amino acids and pep-
tides [21, 22]. Circulating gastrin stimulates acid secretion
by direct action on the parietal cell’s basolateral membrane
CCK
B
receptors (Fig. 2) and indirect action on the gastric
ECL cell’s CCK
B
receptors. ECL cells release histamine in
response to gastrin; histamine in turn stimulates parietal cell
acid secretion by binding to the parietal cell’s basolateral
histamine 2 (H
2
) receptor (see Fig. 2). Parietal cells are also
stimulated to secrete acid by the Vagus nerve through re-
lease of acetylcholine, which activates the muscarinic (M3)
receptor on the parietal cell’s basolateral membrane. A fourth
receptor located on the parietal cell’s basolateral membrane
is activated by prostaglandins, but activation of this receptor
inhibits acid secretion by blocking the histamine pathway
for acid secretion [23]. Histamine-mediated acid secretion
HCl
Gastric Lumen
H
+
/K
+
ATPase
Parietal Cell
+ + +
_
H
+
Basal Surface
Gastrin Histamine Acetylcholine Prostaglandin
CCKB H2R M3R PGR
Fig. 2 Parietal cell physiology. CCKB cholecystokinin B recep-
tor, H2R histamine 2 receptor, M3R muscarinic 3 receptor, PGR
prostaglandin receptor
can also be inhibited pharmacologically by administration
of H
2
-receptor antagonists (H
2
RAs) such as cimetidine, ran-
itidine, nizatidine, or famotidine—agents that remain in use
as highly effective therapy for peptic ulcer disease.
As a consequence of meal-stimulated gastrin release, gas-
tric acid secretion increases and antral pH falls to more acidic
levels. When antral pH is below 3.0, gastric antral D cells
are activated and release somatostatin. Somatostatin in turn
inhibits gastrin release from the antral G cells in paracrine
fashion. The end result is that serum gastrin and gastric acid
secretion fall, prompting antral pH to rise. When antral pH
rises above 3.0, somatostatin release ceases and antral G cell
gastrin release is restored back to basal (premeal) levels.
The presence of such a feedback system for the regulation
of gastric acid secretion also explains the strong correlation
that exists between high antral pH and high levels of serum
gastrin.
Chronic hypergastrinemia: Causes
The causes for chronic hypergastrinemia are listed in
Table 1. They fall into 2 major categories: those associ-
ated with gastrin-secreting tumors (gastrinoma) and those
associated with persistent elevation in antral pH.
Gastrinoma
A gastrin-secreting tumor or gastrinoma may arise sporad-
ically or as part of the multiple endocrine neoplasia-type
1 (MEN-1) syndrome [24]. Typically, the tumors are
multiple and localized predominantly to the pancreas or
duodenal wall. About 50% of the tumors are malignant
and their capacity to secrete gastrin results in serum gastrin
levels whose median value is ∼1000 pg/mL. The resulting
hypergastrinemia—due to the presence of a healthy parietal
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2484 Dig Dis Sci (2007) 52:2482–2489
Table 1 Mechanisms and causes of chronic hypergastrinemia
Mechanism Gastrin level
Gastrin-secreting tumors
Gastrinoma (Zollinger-Ellison syndrome) ++++
Elevated antral pH
Chronic atrophic gastritis/gastric atrophy type A
(pernicious anemia)
++++
Chronic atrophic gastritis type B
(H. pylori-induced pangastritis)
+ or ++
Truncal vagotomy without antrectomy (surgical
therapy of peptic ulcer disease)
+
Chronic antisecretory agents (H
2
receptor
antagonists)
+
Chronic antisecretory agents (proton pump
inhibitors)
++
cell mass—produces gastric acid hypersecretion with basal
acid out (BAO) averaging >15 mEq/hr. Because BAO
is driven to such high levels by the hypergastrinemic
state, maximal acid output (MAO) in response to injected
pentagastrin or histamine is small and thus the ratio of
MAO/BAO is typically below 0.6 [25–27].
Elevation of antral pH
The second major cause for chronic hypergastrinemia is
chronic elevation of antral pH. Elevated antral pH occurs
because of the inability for gastric parietal cells to secrete
acid—a condition that can be induced by destruction of the
parietal cells or by the use of pharmacologic inhibitors of gas-
tric acid secretion. Notably, inhibition of gastric acid secre-
tion protects against the immediate consequences of chronic
hypergastrinemia—peptic ulcer disease and diarrhea—but
alternatively affords the opportunity for circulating gastrin
to provide long-term stimulatory effects on the epithelium of
the digestive tract and its attendant potential for neoplasia.
Chronic atrophic gastritis type A
Chronic atrophic gastritis type A (CAG-A) is a chronic in-
flammatory disease characterized by destruction of the gas-
tric glands and parietal cells. It is believed to be autoimmune
in origin because those with CAG-A have detectable levels
of parietal cell antibodies in the serum [28]. When CAG-
A is severe, as in PA, there is complete destruction of the
parietal cell mass. Destruction of the parietal cells results in
histamine (or pentagastrin)-fast achlorhydria and protection
against the ravages of acid hypersecretion observed in ZES.
Parietal cell destruction also results in failure to secrete in-
trinsic factor with subsequent impairment in the absorption
of dietary vitamin B
12
. Vitamin B
12
deficiency in PA ac-
counts for the development of megaloblastic anemia and/or
peripheral neuropathy owing to destruction of the nerves in
the spinal cord’s posterior columns [29]. Because PA is as-
sociated with chronic achlorhydria, antral pH, and so serum
gastrin levels, are elevated—to levels ≥1000 pg/mL, which
is the range observed in many with ZES [30, 31]. Conse-
quently, serum gastrins >1000 pg/mL are not diagnostic of
either ZES or PA, and the distinction between the 2 requires
clinical correlation. Although no effective therapy for CAG-
A exists, the clinical consequences of PA can be avoided or
largely reversed by oral or parenteral vitamin B
12
supple-
mentation [32].
Chronic atrophic gastritis type B
Chronic atrophic gastritis type B (CAG-B) is a chronic in-
flammatory disease of the stomach due to infection with
H. pylori, a gram-negative, spiral, flagellated bacterium. H.
pylori infection results in damage to the gastric glands by in-
filtrates consisting of both mononuclear and polymorphonu-
clear leukocytes [33]. Infection with H. pylori starts in the
gastric antrum and spreads to the body and fundus, leading
to a pangastritis of the CAG-B type [34–36]. Because the
inflammatory reaction with pangastritis damages the pari-
etal cell mass and releases the acid-inhibiting, interleukin-
1ß, gastric acid secretion is severely inhibited and antral
pH elevated. A consequence of elevated antral pH is, as
expected, chronic hypergastrinemia. Pangastritis can over
time progress to gastric atrophy and intestinal metaplasia, le-
sions that increase the risk of distal gastric adenocarcinoma
and mucosa-associated lymphoid tumor (MALT lymphoma)
[37–39]. Treatment of H. pylori infection with antibiotics
can reverse the inflammatory changes resulting from the or-
ganism, and can reverse MALT lymphoma, but it does not
reverse either gastric atrophy or intestinal metaplasia [3].
(Note: When H. pylori infection is localized to the gastric
antrum, the products of inflammation may promote hyper-
gastrinemia by direct stimulation of antral gastrin release
and/or inhibition of somatostatin release [40–42]. This novel
mechanism may yield modest elevations in gastrin that, in
the presence of a healthy parietal cell mass, increases acid
secretion and promotes peptic ulcer disease of stomach and
duodenum.)
Vagotomy (without antrectomy)
Surgical therapy of peptic ulcer disease before the 1980s
included vagotomy—either truncal, selective, or superselec-
tive [43]. By severing vagal innervation to the gastric parietal
cell mass, acetylcholine release was inhibited and gastric
acid secretion reduced to <1 mEq/hr (see Fig. 2). Inhibi-
tion of gastric acid secretion was accompanied by elevation
of antral pH and hypergastrinemia. Unlike ZES or PA, hy-
pergastrinemia in this setting was modest at ∼200 pg/mL
[44]. Moreover, the origin of the hypergastrinemia was well
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Dig Dis Sci (2007) 52:2482–2489 2485
documented to be due to antral gastrin release since the ad-
dition of antrectomy to vagotomy for control of peptic ulcer
disease abolished gastric acid secretion, but did not produce
hypergastrinemia.
Inhibitors of gastric acid secretion
The pharmacology of peptic ulcer disease began with
antacids as buffers of gastric acid and evolved to inhibitors
of gastric acid secretion, initially with anticholinergics, such
as probanthine [45]. Neither of these therapies was ac-
companied by chronic hypergastrinemia because doses that
raised antral pH had intolerable side effects. For example,
magnesium-containing antacids produced diarrhea, calcium-
containing antacids constipation, and both caused milk-alkali
syndrome and kidney disease; anticholinergic agents pro-
duced tachycardia, urinary retention, dry mouth, and blurry
vision. In the mid-1970s, H
2
RAs came on the market and
were found to be highly efficacious as therapy for peptic ul-
cer disease [45]. When used in double the standard doses for
refractory ulcer disease, they could raise antral pH to ≥4
for ∼6 hours per day and produce a modest chronic hyper-
gastrinemia of ∼200 pg/mL [44]. However, high doses of
H
2
RAs were often eschewed in favor of surgery for peptic
ulcer disease, either vagotomy and pyloroplasty or vagotomy
and antrectomy.
Notably, the acid-suppressing potency of H
2
RAs proved
to be of limited benefit in GERD. In late 1980s, PPIs be-
came available. PPIs are more potent inhibitors of gastric
acid secretion owing to their ability to block the parietal
cell’s apical proton pump (H
+
K
+
,ATPase), the final com-
mon pathway for acid secretion mediated by acetylcholine,
histamine, and gastrin (see Fig. 2). The acid inhibitory po-
tency of the PPIs raised gastric pH > 4 for 12–20 hours per
day and this proved sufficient to control heartburn and heal
the erosions in GERD. GERD, however, was soon shown
to have a high (80% in 1 year) relapse rate, resulting in the
transition of PPI therapy from short to long term to provide
maintenance therapy for GERD [46]. Consequently, antral
pH became elevated and about 20–25% developed modest
degrees of chronic hypergastrinemia (200–400 pg/mL) and
5% developed significant hypergastrinemia (gastrin values
>400 pg/mL) [47, 48].
Chronic hypergastrinemia: Consequences
Gastrinoma
The risks associated with chronic hypergastrinemia are
highly dependent upon the integrity of the gastric parietal
cell mass (Table 2). When the parietal cell mass is healthy—
Table 2 Risks of chronic hypergastrinemia
Mechanism Risk
Intact parietal cell mass
Gastrinoma Zollinger-Ellison syndrome
Aggressive peptic ulcer
disease
Diarrhea/malabsorption
Dysfunctional parietal cell mass
Chronic atrophic gastritis/gastric
atrophy type A (pernicious
anemia)
Gastric carcinoid tumors
Chronic atrophic gastritis type B
(H. pylori-induced pangastritis)
+ or ++
Truncal vagotomy without
antrectomy (surgical therapy of
peptic ulcer disease)
+
Chronic antisecretory agents (H
2
receptor antagonists)
+
Chronic antisecretory agents
(proton pump inhibitors)
++
as in the presence of a gastrinoma—gastric acid output is
high and leads to the ZES. ZES is characterized by an ag-
gressive form of peptic ulcer disease, severe diarrhea, or
both [24]. The peptic ulcers in ZES may be single and lo-
cated in the duodenal bulb, but are often multiple and in
atypical bowel locations. More importantly, peptic ulcers in
ZES have a high risk of complications, including bowel per-
foration, hemorrhage, and obstruction and are often accom-
panied by severe diarrhea. Diarrhea without obvious peptic
ulcer disease also occurs in about ∼7% of those with ZES.
This is due to excessive acidification of the duodenum and
lower small bowel, resulting in damage to the absorptive mu-
cosa, inactivation of pancreatic enzymes, and precipitation
of bile salts. Consequently, the diarrhea of ZES has inflam-
matory, osmotic, and malabsorptive features. The diagnosis
of ZES is usually made by characteristic clinical presenta-
tion, high serum gastrin, and elevated BAO. Some with ZES
may have normal or near-normal serum gastrin levels, ne-
cessitating performance of an intravenous secretin test for
diagnosis [49]. Secretin increases serum gastrin in ZES to
levels ≥200 pg/mL above basal levels, but has no effect on or
reduces serum gastrin for non-ZES conditions. Confirmation
of ZES requires a search for the primary tumor using imaging
techniques such computerized axial tomography, ultrasonog-
raphy, arteriography, or more somatostatin receptor scintig-
raphy in combination with selective arterial secretagogue
(secretin or calcium) injection testing [50]. Treatment is best
managed with resection; however, when this is not possible,
chemotherapy is used for tumor control and high-dose PPIs
are used for protection against the ravages of gastric acid
hypersecretion.
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2486 Dig Dis Sci (2007) 52:2482–2489
Gastric carcinoids
In contrast to gastrinoma, chronic hypergastrinemia in the
presence of a dysfunctional parietal cell mass has little or
no effect on gastric acid secretion; consequently, peptic ul-
cer disease and diarrhea are not present. However, chronic
hypergastrinemia can produce more subtle long-term effects
because of its promotion of growth in the digestive tract ep-
ithelium. In this respect, chronic hypergastrinemia has been
associated with particular neoplasms of the digestive tract—
one being gastric carcinoids [51].
Carcinoids are tumors of ECL cell origin and can arise
anywhere along the digestive tract. Type I carcinoid, the
most common (75%), is associated with CAG-A. Type II is
associated with ZES and MEN-1 syndrome, and type III is
sporadic. Both types I and II carcinoids occur in the setting of
hypergastrinemia, and because gastrin stimulates ECL cell
proliferation via its CCK
B
receptors, hypergastrinemia has
been considered to be the primary etiology [52, 53]. Further
support for this concept is provided by the fact that 7% of pa-
tients with CAG-A, and many with PA, develop carcinoids,
while another 30% have ECL cell hyperplasia [54, 55]. In
addition, gastric carcinoids occur with increased frequency
in ZES associated with MEN-1. Last, those with MEN-1
but without gastrinoma do not have an increase in gastric
carcinoids. Yet, patients with chronic hypergastrinemia from
ZES without MEN-1 rarely develop carcinoids. Taken to-
gether, the data suggest that gastrin is etiologic for ECL cell
hyperplasia but is itself insufficient to induce ECL cell con-
version from hyperplasia to neoplasia. Neoplasia appears to
require hypergastrinemia to be accompanied by a neoplasia-
inducing cofactor, such as the loss of the tumor suppressor
gene, menin, in MEN-1 syndrome or overexpression of the
tumor growth promoter, BCL-2, in atrophic gastritis [56, 57].
These concepts derive additional support from observations
made in those on chronic PPI therapy.
Chronic elevation of antral pH by pharmacologic in-
hibitors of gastric acid secretion refocused attention on
chronic hypergastrinemia and its potential for long-term con-
sequences. This concern came to the fore early after the in-
troduction of the PPIs when studies of high-dose PPIs in
female rats resulted in ECL cell hyperplasia in 30–40% of
the animals and gastric carcinoids in 25% over a 2-year pe-
riod. These phenomena were reproduced in animals treated
with H
2
RAs or surgical removal of the parietal cell mass and
prevented in animals pretreated with antrectomy or the gas-
trin antagonist, proglumide [45, 58]. A black box warning
was initially affixed to PPI therapy by the US Food and Drug
Association, but was subsequently removed when high-dose
PPIs did not induce similar results in other species, including
humans. PPIs have now been available for 15 years in the
United States. There is a well-documented association with
ECL hyperplasia, but evidence of an increased frequency of
gastric carcinoids is lacking [59, 60]. These data in effect
support the concept that hypergastrinemia promotes ECL
cell hyperplasia but not neoplasia. The discrepant findings
for the effects of PPIs in rats are attributed to a species spe-
cific effect, probably because rats have a high density of ECL
cells that are exquisitely sensitivity to gastrin’s trophic effect
[56, 61–63].
Colon cancer
An association between chronic hypergastrinemia and colon
carcinoma was reported in 1998 based on a large prospective
epidemiologic study of H. pylori-infected patients. The re-
sults showed that mild elevations of serum gastrin increased
colorectal cancer risk ∼4-fold over a 15-year period [64].
Indeed, circulating levels of nonamidated, but not amidated,
gastrin precursors were previously reported to be increased
in patients with colorectal cancer [65]. In addition, some
colon cancer cells possess CCK
B
(gastrin) receptors, which
have been shown to induce cell proliferation when activated
by nonamidated gastrins. Moreover, colon cancer cells can
themselves express nonamidated gastrins and as such can
promote growth in an autocrine fashion as well as an en-
docrine (systemic) fashion [66–72]. In addition, transgenic
mice expressing high levels of progastrin do not develop
colon cancer, but have an increase in susceptibility to
azoxymethane-induced colon carcinogenesis; this suggests
that progastrin acts as a cocarcinogen that increases the
susceptibility to colon cancer. More recent work has es-
tablished that progastrin exerts its cocarcinogenic effects at
physiologically relevant concentrations, that is, <1–5 nmol,
levels that are measurable in subjects with colon cancer
and hypergastrinemia [73]. In contrast to the effects of
nonamidated gastrins, amidated gastrin, namely, gastrin-17,
has antiproliferative and proapoptotic effects in human colon
cancer cell lines expressing the CCK
B
receptor; this has
been shown to result in inhibition of colon tumor growth in
hypergastrinemic severe combined immunodeficiency mice
[74]. Hypergastrinemia alone was incapable of inducing
colon carcinoma, but promotes progression of adenoma size
and malignant potential in the APC (Min1/ +) mouse model
of familial adenomatous polyposis [75]. Taken together,
these data support the concept that chronic hypergastrinemia
per se is not carcinogenic, but as a proliferative stimulus it
can expand the pool of cells at risk for cancer. In this respect,
it is a cocarcinogen that may promote or increase the rate of
growth of colon cancer in susceptible patient populations.
One such population, as suggested by the Thorburn report,
may be those infected with H. pylori, which is listed as a class
I carcinogen by the World Health Organization [64]. These
concepts are consistent with the fact that an increase in colon
carcinogenesis has not been observed in hypergastrinemic
patients with PA and ZES nor has there been documentation
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Dig Dis Sci (2007) 52:2482–2489 2487
that patients on acid suppressing medications, including
PPIs, have an increased risk of colon cancer [76, 77].
Summary
Chronic hypergastrinemia is no longer an uncommon phe-
nomenon. When associated with an intact parietal cell mass
as in ZES, it results in acid hypersecretion and clinically
manifests as peptic ulcer disease and/or diarrhea. When as-
sociated with an impaired parietal cell mass as in PA, PPI
therapy, or H. pylori-induced pangastritis, it is associated
with acid hyposecretion. Acid hyposecretion protects against
the ravages of acid hypersecretion but enables the more sub-
tle proliferative effects of gastrin to proceed. Gastrin’s pro-
liferative effects are evident histologically as gastric ECL
cell hyperplasia in humans and animals and in animals they
promote neoplasia when combined with a known carcino-
gen. Although progrowth, gastrin itself does not appear to
be mutagenic. Consequently, clinicians should remain aware
of the continued concern that exists about chronic hypergas-
trinemia, but take comfort in the evidence to date that the
phenomenon itself promotes neoplasia.
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