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Chronic Hypergastrinemia: Causes and Consequences

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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 conditions of chronic hypergastrinemia as exemplified by the Zollinger-Ellison syndrome and pernicious anemia. More recently, the concern about the potential risk of chronic hypergastrinemia has risen because of the widespread use of proton pump inhibitors for maintenance therapy in reflux esophagitis. For this reason, we present a concise overview of the origin, causes, and potential risks of chronic hypergastrinemia.
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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) [37]. 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 [811]. 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)[1215]. 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
[1719]. 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 [2527].
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 [3436]. 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)
[3739]. 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 [4042]. 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, 6163].
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 [6672]. 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.
References
1. Hirschowitz BI (1997) Zollinger-Ellison syndrome: pathogenesis,
diagnosis, and management. Am J Gastroenterol 92:44S-48S; dis-
cussion 49S-50S
2. Sculco D, Bilgrami S (1997) Pernicious anemia and gastric carci-
noid tumor: case report and review. Am J Gastroenterol 92:1378–
1380
3. Annibale B, Aprile MR, D’Ambra G, Caruana P, Bordi C, Delle
Fave G (2000) Cure of Helicobacter pylori infection in atrophic
body gastritis patients does not improve mucosal atrophy but re-
duces hypergastrinemia and its related effects on body ECL-cell
hyperplasia. Aliment Pharmacol Ther 14:625–634
4. Arroyo Villarino MT, Lanas Arbeloa A, Esteva Diaz F, Ortego
Fernandez de Retana J, Sainz Samitier R (1997) Effects of long-
term treatment with lansoprazole and omeprazole on serum gastrin
and the fundic mucosa. Rev Esp Enferm Dig 89:347–356
5. Freston JW (1997) Long-term acid control and proton pump in-
hibitors: interactions and safety issues in perspective. Am J Gas-
troenterol 92:51S-55S; discussion 55S-57S
6. Garnett WR (1998) Considerations for long-term use of proton-
pump inhibitors. Am J Health Syst Pharm 55:2268–2279
7. Tokushima H, Tamura H, Murakawa M, Matsumura O, Itakura Y,
Itoyama S, Mitarai T, Isoda K (1998) Eradication of Helicobacter
pylori restores elevation of serum gastrin concentrations in patients
with end-stage renal disease. Intern Med 37:435–439
8. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH (2000)
Review article: Potential gastrointestinal effects of long-term acid
suppression with proton pump inhibitors. Aliment Pharmacol Ther
14:651–668
9. McCloy RF, Arnold R, Bardhan KD, Cattan D, Klinkenberg-Knol
E, Maton PN, Riddell RH, Sipponen P, Walan A (1995) Pathophys-
iological effects of long-term acid suppression in man. Dig Dis Sci
40:96S-120S
10. Pohle T, Domschke W (2000) Results of short-and long-term med-
ical treatment of gastroesophageal reflux disease (GERD). Lan-
genbecks Arch Surg 385:317–323
11. Reilly JP (1999) Safety profile of the proton-pump inhibitors. Am
J Health Syst Pharm 56:S11–17
12. Dickinson CJ, Yamada T (1991) Gastrin-amidating enzyme in the
porcine pituitary and antrum. Characterization of molecular forms
and substrate specificity. J Biol Chem 266:334–338
13. Dockray GJ, Varro A, Dimaline R, Wang T (2001) The gas-
trins: Their production and biological activities. Annu Rev Physiol
63:119–139
14. Hilsted L, Rehfeld JF (1987) Alpha-carboxyamidation of antral
progastrin. Relation to other post-translational modifications. J
Biol Chem 262:16953–16957
15. Rahier J, Pauwels S, Dockray GJ(1987) Biosynthesis of gastrin.
Localization of the precursor and peptide products using electron
microscopic-immunogold methods. Gastroenterology 92:1146–
1152
16. Noble F, Wank SA, Crawley JN, Bradwejn J, Seroogy KB, Hamon
M, Roques BP (1999) International Union of Pharmacology. XXI.
Structure, distribution, and functions of cholecystokinin receptors.
Pharmacol Rev 51:745–781
17. Koh TJ, Dockray GJ, Varro A, Cahill RJ, Dangler CA, Fox JG,
Wang TC (1999) Overexpression of glycine-extended gastrin in
transgenic mice results in increased colonic proliferation. J Clin
Invest 103:1119–1126
18. Koh TJ, Goldenring JR, Ito S, Mashimo H, Kopin AS, Varro A,
Dockray GJ, Wang TC (1997) Gastrin deficiency results in altered
gastric differentiation and decreased colonic proliferation in mice.
Gastroenterology 113:1015–1025
19. Seva C, Dickinson CJ, Yamada T (1994) Growth-promoting effects
of glycine-extended progastrin. Science 265:410–412
20. Nagata A, Ito M, Iwata N, Kuno J, Takano H, Minowa O, Chihara
K, Matsui T, Noda T (1996) G protein-coupled cholecystokinin-
B/gastrin receptors are responsible for physiological cell growth of
the stomach mucosa in vivo. Proc Natl Acad Sci USA 93:11825–
11830
21. Johnson LR, Lichtenberger LM, Copeland EM, Dudrick SJ,
Castro GA (1975) Action of gastrin on gastrointestinal structure
and function. Gastroenterology 68:1184–1192
22. Lichtenberger LM, Delansorne R, Graziani LA (1982) Importance
of amino acid uptake and decarboxylation in gastrin release from
isolated G cells. Nature 295:698–700
23. Feldman M (2002) Gastric secretion. In: Feldman MFL, Sleisenger
MH (eds) Seisenger & Fordtran’s Gastrointestinal and Liver Dis-
ease: Pathophysiology/Diagnosis/Management, vol 1. Saunders,
Philadelphia, pp 715–731
24. Pisegna J (2002) Zollinger-Ellison syndrome and other hypersecre-
tory states. In: Feldman MFL, Sleisenger MH (eds) Sleisenger
and Fordtran’s Gastrointestinal and Liver Disease: Pathophysi-
ology/Diagnosis/Management, vol 1. Saunders, Philadelphia, pp
782–796
25. Berger AC, Gibril F, Venzon DJ, Doppman JL, Norton JA, Bartlett
DL, Libutti SK, Jensen RT, Alexander HR (2001) Prognostic value
of initial fasting serum gastrin levels in patients with Zollinger-
Ellison syndrome. J Clin Oncol 19:3051–3057
26. Lehy T, Cadiot G, Mignon M, Ruszniewski P, Bonfils S (1992)
Influence of multiple endocrine neoplasia type 1 on gastric en-
docrine cells in patients with the Zollinger-Ellison syndrome. Gut
33:1275–1279
27. Roy PK, Venzon DJ, Shojamanesh H, Abou-Saif A, Peghini P,
Doppman JL, Gibril F, Jensen RT (2000) Zollinger-Ellison syn-
drome. Clinical presentation in 261 patients. Medicine 79:379–
411
28. Lo CC HP, Lo GH, Lai KH, Tseng HH, Lin CK, Chan HH, Tsai
WL, Chen WC, Peng NJ (2005) Implications of anti-parietal cell
Springer
2488 Dig Dis Sci (2007) 52:2482–2489
antibodies and anti-Helicobacter pylori antibodies in histological
gastritis and patient outcome. World J Gastroenterol 11:4715–
4720
29. Toh B-H AF (2004) Pernicious anemia. Autoimmunity 37:357–
361
30. Carmel R (1988) Pepsinogens and other serum markers in perni-
cious anemia. Am J Clin Pathol 90:442–445
31. Lanzon Miller S, Pounder RE, Hamilton MR, Chronos NA, Ball S,
Mercieca JE, Olausson M, Cederberg C (1987) Twenty-four-hour
intragastric acidity and plasma gastrin concentration in healthy
subjects and patients with duodenal or gastric ulcer, or pernicious
anaemia. Aliment Pharmacol Ther 1:225–237
32. Nyholm E TP, Swain D, Cunningham B, Daly S, Nightingale P,
FeganC (2003) Oral vitamin B12 can change our practice. Postgrad
Med J 79:218–219
33. Peterson WL, Graham DY (2002) Helicobacter pylori. In: Feldman
MFL, Sleisenger MH (eds) Sleisenger & Fordtran’s Gastrointesti-
nal and Liver Disease: Pathophysiology/Diagnosis/Management,
vol 1. Saunders, Philadelphia, pp 732–746
34. Annibale B, Marignani M, Azzoni C, D’Ambra G, Caruana P,
D’Adda T, Delle Fave G, Bordi C (1997) Atrophic body gastri-
tis: Distinct features associated with Helicobacter pylori infection.
Helicobacter 2:57–64
35. Dunn BE (1993) Pathogenic mechanisms of Helicobacter pylori.
Gastroenterol Clin North Am 22:43–57
36. Park SM, Yoo BC, Lee HR, Yoon JH, Cha YJ (1993) Antral He-
licobacter pylori infection, hypergastrinemia and peptic ulcers:
Effect of eradicating the organism. Korean J Intern Med 8:19–24
37. Fox JG WT, Rogers AB, Poutahidis T, Ge Z, Taylor N,
Dangler CA, Israel DA, Krishna U GK, Peek Jr RM (2003) Host
and microbial constituents influence Helicobacter pylori-induced
cancer in a murine model of hypergastrinemia. Gastroenterology
124:1879–1890
38. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, Havu N, Festen HP,
Liedman B, Lamers CB, Jansen JB, Dalenback J, Snel P, Nelis
GF, Meuwissen SG (1996) Atrophic gastritis and Helicobacter
pylori infection in patients with reflux esophagitis treated with
omeprazole or fundoplication. N Engl J Med 334:1018–1022
39. Moayyedi P, Wason C, Peacock R, Walan A, Bardhan K, Axon
AT, Dixon MF (2000) Changing patterns of Helicobacter pylori
gastritis in long-standing acid suppression. Helicobacter 5:206–
214
40. Gordon D (2000) CagA protein from Helicobacter pylori is a
Trojan horse to epithelial cells. Gastroenterology 118:817
41. Kim JH, Park HJ, Cho JS, Lee KS, Lee SI, Park IS, Kim CK (1999)
Relationship of CagA to serum gastrin concentrations and antral
G, D cell densities in Helicobacter pylori infection. Yonsei Med J
40:301–306
42. Konturek PC, Bielanski W, Konturek SJ, Hahn EG (1999) Heli-
cobacter pylori associated gastric pathology. J Physiol Pharmacol
50:695–710
43. Rege RV, Jones DB (2002) Current role of surgery in pep-
tic ulcer disease. In Feldman MFL, Sleisenger MH (eds)
Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Patho-
physiology/Diagnosis/Management, vol 1. Saunders, Philadelphia,
pp 797–809
44. Trudeau WL, McGuigan JE (1970) Serum gastrin levels in patients
with peptic ulcer disease. Gastroenterology 59:6–12
45. Spechler SJ (2002) Peptic ulcer disease and its complica-
tions. In Feldman MFL, Sleisenger MH(eds) Sleisenger &
Fordtran’s Gastrointestinal and Liver Disease: Pathophysiol-
ogy/Diagnosis/Management, vol 1. Saunders, Philadelphia, pp
747–781
46. Orlando R (1999) Reflux esophagitis. In Yamada T, Alpers DH,
Laine L, et al. (eds) Textbook of Gastroenterology. J.B. Lippincott
Williams & Wilkins, Philadelphia, pp 1235–1263
47. Koop HAR (1991) Long-term maintenance treatment of reflux
esophagitis with omeprazole: Prospective study in patients with
H2-blocker-resistant esophagitis. Dig Dis Sci 36:552–557
48. Lamberts R, Brunner G, Solcia E (2001) Effects of very long (up
to 10 years) proton pump blockade on human gastric mucosa.
Digestion 64:205–213
49. Hung PDSM, Mihas AA (2003) Zollinger-Ellison syndrome. Curr
Treat Options Gastroenterol 6:163–170
50. Imamura M, Komoto I, Ota S (2006) Changing treatment strategy
for gastrinoma in patients with Zollinger-Ellison syndrome. World
J Surg 30:1–11
51. Modlin IM, Lye KD, Kidd M (2003) Carcinoid tumors of the
stomach. Surg Oncol 12:153–172
52. Modlin IM, Gilligan CJ, Lawton GP, Tang LH, West AB, Darr
U (1995) Gastric carcinoids. The Yale Experience. Arch Surg
130:250–255; discussion 255–256
53. Thomas RM, Baybick JH, Elsayed AM, Sobin LH (1994) Gastric
carcinoids. An immunohistochemical and clinicopathologic study
of 104 patients. Cancer 73:2053–2058
54. Moses RE, Frank BB, Leavitt M, Miller R (1986) The syndrome of
type A chronic atrophic gastritis, pernicious anemia, and multiple
gastric carcinoids. J Clin Gastroenterol 8:61–65
55. Spoelstra-de Man AM, Wagenaar SS, vander Sluys Veer A,
Brouwer CB (2000) Relationship between pernicious anaemia and
gastric neuroendocrine cell disorders. Neth J Med 56:56–62
56. Bordi C, D’Adda T, Azzoni C, Aprile MR, Pilato FP, Ferraro G
(1997) Neuroendocrine proliferation in the gastric mucosa: Biolog-
ical behaviour and management. Verh Dtsch Ges Pathol 81:103–
110
57. Cadiot G, Laurent-Puig P, Thuille B, Lehy T, Mignon M,
Olschwang S (1993) Is the multiple endocrine neoplasia type 1
gene a suppressor for fundic argyrophil tumors in the Zollinger-
Ellison syndrome? Gastroenterology 105:579–582
58. Carlsson E, Larsson H, Mattsson H, Ryberg B, Sundell G (1986)
Pharmacology and toxicology of omeprazole—With special refer-
ence to the effects on the gastric mucosa. Scand J Gastroenterol
Suppl 118:31–38
59. Hirschowitz BI, Haber MM (2001) Helicobacter pylori effects
on gastritis, gastrin and enterochromaffin-like cells in Zollinger-
Ellison syndrome and non-Zollinger-Ellison syndrome acid hyper-
secretors treated long-term with lansoprazole. Aliment Pharmacol
Ther 15:87–103
60. Solcia E, Rindi G, Silini E, Villani L (1993) Enterochromaffin-like
(ECL) cells and their growths: relationships to gastrin, reduced acid
secretion and gastritis. Baillieres Clin Gastroenterol 7:149–165
61. Creutzfeldt W (1988) The achlorhydria-carcinoid sequence: Role
of gastrin. Digestion 39:61–79
62. Peghini PL, Annibale B, Azzoni C, Milione M, Corleto V, Gibril
F, Venzon DJ, Delle Fave G, Bordi C, Jensen RT (2002) Effect of
chronic hypergastrinemia on human enterochromaffin-like cells:
Insights from patients with sporadic gastrinomas.Gastroenterology
123:68–85
63. Tielemans Y, Hakanson R, Sundler F, Willems G (1989) Prolifera-
tion of enterochromaffinlike cells in omeprazole-treated hypergas-
trinemic rats. Gastroenterology 96:723–729
64. Thorburn CM, Friedman GD, Dickinson CJ, Vogelman JH,
Orentreich N, Parsonnet J (1998) Gastrin and colorectal cancer:
a prospective study. Gastroenterology 115:275–280
65. Ciccotosto GD, McLeish A, Hardy KJ, Shulkes A (1995) Expres-
sion, processing, and secretion of gastrin in patients with colorectal
carcinoma. Gastroenterology 109:1142–1153
66. Schmitz F, Otte JM, Stechele HU, Reimann B, Banasiewicz T,
Folsch UR, Schmidt WE, Herzig KH (2001) CCK-B/gastrin re-
ceptors in human colorectal cancer. Eur J Clin Invest 31:812–820
67. Singh P, Velasco M, Given R, Varro A, Wang TC (2000) Progastrin
expression predisposes mice to colon carcinomas and adenomas
Springer
Dig Dis Sci (2007) 52:2482–2489 2489
in response to a chemical carcinogen. Gastroenterology 119:162–
171
68. Singh P, Velasco M, Given R, Wargovich M, Varro A, Wang TC
(2000) Mice overexpressing progastrin are predisposed for devel-
oping aberrant colonic crypt foci in response to AOM. Am J Physiol
Gastrointest Liver Physiol 278:G390–399
69. Stepan VM, Sawada M, Todisco A, Dickinson CJ (1999) Glycine-
extended gastrin exerts growth-promoting effects on human colon
cancer cells. Mol Med 5:147–159
70. Singh P, Walker JP, Townsend Jr CM , Thompson JC (1986) Role
of gastrin and gastrin receptors on the growth of a transplantable
mouse colon carcinoma (MC-26) in BALB/c mice. Cancer Res
46:1612–1616
71. Upp Jr JR, Singh P, Townsend Jr CM, Thompson JC (1989)
Clinical significance of gastrin receptors in human colon cancers.
Cancer Res 49:488–492
72. Yapp R, Modlin IM, Kumar RR, Binder HJ, Dubrow R (1992)
Gastrin and colorectal cancer. Evidence against an association.
Dig Dis Sci 37:481–484
73. Cobb S, Wood T, Ceci J, Varro A, Velasco M, Singh P (2004)
Intestinal expression of mutant and wild-type progastrin signifi-
cantly increases colon carcinogenesis in response to azoxymethane
in transgenic mice. Cancer 100:1311–1323
74. Muerkoster S, Isberner A, Arlt A, Witt M, Reimann B, Blaszczuk
E, Werbing V, Folsch UR, Schmitz F, Schafer H (2005) Gastrin sup-
presses growth of CCK2 receptor expressing colon cancer cells by
inducing apoptosis in vitro and in vivo. Gastroenterology 129:952–
968
75. Watson SA, Smith AM (2001) Hypergastrinemia promotes ade-
noma progression in the APC(Min-/ +) mouse model of familial
adenomatous polyposis. Cancer Res 61:625–631
76. Wang TC, Dockray GJ (1999) Lessons from genetically engineered
animal models. I. Physiological studies with gastrin in transgenic
mice. Am J Physiol 277:G6–11
77. Orbuch M, Venzon DJ, Lubensky IA, Weber HC, Gibril F, Jensen
RT (1996) Prolonged hypergastrinemia does not increase the fre-
quency of colonic neoplasia in patients with Zollinger-Ellison syn-
drome. Dig Dis Sci 41:604—613
Springer
... However, their intense gastric-acid suppressive activity has raised concerns about their association with carcinogenesis (34). These concerns are due to the fact that PPIs can induce hypergastrinemia and bacterial overgrowth in the gut (35). One of the most prevalent carcinomas triggered by PUD and its related therapeutics is CCA. ...
... Hypergastrinemia is considered to be the major mechanism associated with PPI-induced carcinogenesis. It causes a persistent elevation in gastric antral pH and spurs cell proliferation leading to carcinogenesis and tumor growth (35). Recent studies have demonstrated that PPI use is associated with peri-ampullary tumors (61). ...
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The marked drop in the frequency of Helicobacter pylori infection resulting from the use of antibiotics and potent anti-acid medications has substantially lowered the prevalence of peptic ulcer disease in recent decades. Management of this condition, however, is challenging because of the escalating perils of antibiotic resistance and the abuse of anti-inflammatory drugs. For example, the increased prevalence of cholangiocarcinomas may associate with this peptic ulcer disease management including the prolonged use of proton pump inhibitors. Cholangiocarcinoma is one of the most lethal cancers and accounts for almost 15% of all hepatic malignancies. This review provides a concise summary of the latest findings in the pathogenetic mechanisms of cholangiocarcinoma, essentially focusing on peptic ulcer disease and its associated therapies. We also suggest interventions that may reduce Helicobacter pylori infection and peptic ulcers with the bacteriostatic agent, melatonin. Melatonin treatment may reduce the incidence of this devastating cancer or improve the outcome of individuals that develop this disease.
... Moderate gastrin elevations (approximately 200-400 pg/mL) have been observed with the long-term use of PPIs, and no association with serious pathology has been reported. 44 In the present study, serum gastrin levels increased proportionally to the dosage and duration of PCAB administration. Overall, the PCAB group had higher serum gastrin levels than the PPI group. ...
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Background/aims: Gastroesophageal reflux disease (GERD) is typically managed based on the clinical phenotype. We evaluated the efficacy and safety of potassium-competitive acid blockers (PCABs) in patients with various clinical GERD phenotypes. Methods: Core databases were searched for studies comparing PCABs and proton pump inhibitors (PPIs) in clinical GERD phenotypes of erosive reflux disease (ERD), non-erosive reflux disease (NERD), PPI-resistant GERD and night-time heartburn. Additional analysis was performed based on disease severity and drug dosage, and pooled efficacy was calculated. Results: In 9 randomized controlled trials (RCTs) evaluating the initial treatment of ERD, the risk ratio for healing with PCABs versus PPIs was 1.09 (95% CI, 1.04-1.13) at 2 weeks and 1.03 (95% CI, 1.00-1.07) at 8 weeks, respectively. PCABs exhibited a significant increase in both initial and sustained healing of ERD compared to PPIs in RCTs, driven particularly in severe ERD (Los Angeles grade C/D). In 3 NERD RCTs, PCAB was superior to placebo in proportion of days without heartburn. Observational studies on PPI-resistant symptomatic GERD reported symptom frequency improvement in 86.3% of patients, while 90.7% showed improvement in PPIresistant ERD across 5 observational studies. Two RCTs for night-time heartburn had different endpoints, limiting meta-analysis. Pronounced hypergastrinemia was observed in patients treated with PCABs. Conclusions: Compared to PPIs, PCABs have superior efficacy and faster therapeutic effect in the initial and maintenance therapy of ERD, particularly severe ERD. While PCABs may be an alternative treatment option in NERD and PPI-resistant GERD, findings were inconclusive in patients with night-time heartburn.
... Similarly, the %Time pH >4 at nighttime was significantly higher in the zastaprazan 40 mg dose group of the MAD study (89.28 ± 9.12%) compared to the esomeprazole 40 mg dose group (56.56 ± 22.47%), indicating a stronger acid suppression compared to esomeprazole at nighttime.The serum gastrin levels increased to a peak level approximately eight hours after the single and multiple oral administrations of zastaprazan and esomeprazole and decreased to nearly baseline levels at 24 h(Figures S1 and S2). Four subjects (one subject in the zastaprazan 20 mg dose group and three subjects in the esomeprazole 40 mg dose group) in the MAD study showed a peak serum gastrin level over 400 ng/mL, a criterion for hypergastrinemia.22 There was no statistically significant difference between G max , AUEG last after all doses of zastaprazan and those after the 40 mg of esomeprazole in the SAD and MAD studies, except for AUEG last of the 20 and 40 mg dose groups in the SAD study. ...
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Background Zastaprazan (JP‐1366) is a novel potassium‐competitive acid blocker with favourable preclinical safety and efficacy profile being developed for the treatment of acid‐related diseases. Aims To investigate the safety, tolerability, pharmacodynamics and pharmacokinetics of zastaprazan. Methods A randomised, open‐label, placebo‐ and active‐controlled, single and multiple ascending dose clinical trial was conducted in healthy Korean male subjects. Intragatric pH and serum gastrin were measured to assess the pharmacodynamics, while serial blood and urine samples were collected to assess the pharmacokinetics. Pharmacogenomic evaluation was conducted to explore genetic variants, which can affect the pharmacodynamics and pharmacokinetics. Safety and tolerability including hepatotoxicity were evaluated. Results Suppression of gastric acid secretion increased as the dose of zastaprazan increased. The percentage of time that gastric pH was over 4 (%Time pH >4) with zastaprazan 20 mg (85.19%) and 40 mg (91.84%) were similar to or greater than that with esomeprazole 40 mg (72.06%). Zastaprazan was rapidly absorbed within 2 h and eliminated with a half‐life of 6–10 h. Pharmacogenomic analysis found no genetic variant of drug metabolising enzymes including CYP2C19 or drug transporters associated with the exposure of zastaprazan. Zastaprazan was well tolerated with no clinically significant changes in safety and tolerability assessments. Conclusions Zastaprazan was safe and well tolerated after a single oral dose up to 60 mg and multiple oral doses up to 40 mg. It also showed rapid, potent suppression of gastric acid secretion. Pharmacodynamic and pharmacokinetic profile of zastaprazan was suitable for treatment of patients with acid‐related diseases.
... The hypothesized mechanisms include bacterial overgrowth, the formation of N-nitroso compounds, lipopolysaccharides, and deoxycholic acid, which have been linked to the development of liver cancer [37][38][39][40][41][42][43]. Additionally, higher gastrin levels following PPI or H2RA use may be associated with gastrointestinal malignancies [44,45]. Therefore, it is reasonable to assume that a link between acid-suppressive medication use and cancer development may be based on differing mechanisms. ...
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N-Nitrosodimethylamine (NDMA), a carcinogenic chemical, has recently been identified in ranitidine. We conducted a population-based study to explore ranitidine use and cancer emergence over time. Using the Taiwan National Health Insurance Research Database, a population-based cohort study was conducted. A total of 55,110 eligible patients who received ranitidine between January 2000 and December 2018 were enrolled in the treated cohort. We conducted a 1:1 propensity-score-matching procedure to match the ranitidine-treated group with the ranitidine-untreated group and famotidine controls for a longitudinal study. The association of ranitidine exposure with cancer outcomes was assessed. A multivariable Cox regression analysis that compared cancer risk with the untreated groups revealed that ranitidine increased the risk of liver (hazard ratio (HR): 1.22, 95% confidence interval (CI): 1.09–1.36, p < 0.001), lung (HR: 1.17, CI: 1.05–1.31, p = 0.005), gastric (HR: 1.26, CI: 1.05–1.52, p = 0.012), and pancreatic cancers (HR 1.35, CI: 1.03–1.77, p = 0.030). Our real-world observational study strongly supports the pathogenic role of NDMA contamination, given that long-term ranitidine use is associated with a higher likelihood of liver cancer development in ranitidine users compared with the control groups of non-ranitidine users treated with famotidine or proton-pump inhibitors.
... The elevated gastrin levels are within the expected range reported in PPI therapy (200-400 pg/mL). [19][20][21] In addition, no severe or clinically significant AEs were observed, which indicates that the selected dose of 200 mg of tegoprazan is well tolerated in healthy men under both fasting and fed conditions. Although C max was decreased by a meal, no significant differences were found in AUC 0-t , pharmacodynamic parameters and safety profiles between fed and fasting conditions. ...
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Purpose Tegoprazan is a potassium-competitive acid blocker (P-CAB) that is designed to treat acid-related diseases through a fundamentally different mechanism than that of proton pump inhibitors (PPIs). Because PPIs inhibit only activated parietal cell H⁺/K⁺ adenosine triphosphatase, stimulation of parietal cells by a meal is necessary for optimal results. In contrast, P-CABs can inactivate proton pumps without acid activation and bind to both activated and inactivated adenosine triphosphatase. This study evaluates the effect of food consumption on the pharmacokinetic and pharmacodynamic properties of tegoprazan after a single oral dose in healthy men. Methods In this open-label, 2-period crossover study, 24 healthy men were randomized to 1 of 2 treatment sequence groups: administration of tegoprazan under the fasting condition and administration of tegoprazan under the fed condition. The dosing periods of both sequence groups were separated by a washout period of 7 days. At each dosing period, the participants received a single dose of 200 mg of tegoprazan followed by pharmacokinetic and pharmacodynamic analysis. Findings After the oral administration of 200 mg tegoprazan, the Cmax was decreased and delayed under the fed condition compared with that of the fasting condition. However, no significant differences were observed in the AUC and the time of gastric acid suppression (inhibition of integrated acidity) during 24 hours. Implications The pharmacokinetic and pharmacodynamic properties of tegoprazan are independent of food effect; thus, tegoprazan could be administered regardless of the timing of food consumption in patients. ClinicalTrials.gov identifier: NCT01830309.
... La cause probable de ce type d'eczéma est une hypercalcémie (confirmée) liée à un ou plusieurs nodules thyroïdiens défaillant [1]. L'excès de calcium est éliminé par les reins (1/3) et par le système digestif (2/3), entrainant la sécrétion de gastrine puis d'histamine [2]. La consommation d'IPP limite l'élimination de l'histamine, celle-ci en excès avec un taux haut de gastrine (hormone trophique, c'est à dire servant de nourriture notamment pour les cellules épithéliales) peut causer une sensibilisation accrue aux allergies et peut expliquer l'eczéma aux extrémités (pieds/mains). ...
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This prospective study describes the occurrence, morphology and localisation of type 1 abomasal ulcers (AU1) in various diseases of buffaloes and cattle. The carcasses were examined to confirm the cause of death. The abomasa were examined for AU1 and their characteristics. The AU1 were categorised into four subtypes, 1a, 1b, 1c and 1d, as per standard procedure. Traumatic reticuloperitonitis/pericarditis, reticular diaphragmatic hernia, intestinal obstruction, peritonitis, bronchopneumonia and theileriosis were the common causes for AU1. The overall prevalence of AU1 was 62.9%, which did not differ significantly with species and age. The prevalence of acute ulcers (1a and 1b) was significantly higher than that of chronic ulcers (1c and 1d). Most AU1 were located in the caudal third of abomasal body on parietal surface along the greater curvature. Most of the 1a ulcers were located in the pylorus, while 1b, 1c and 1d were located in the abomasal body. The overall prevalence of AU1 was lower (P<0.05) in the fundus than in other anatomical regions of the abomasum. Type 1b ulcers were more numerous than other subtypes. It was concluded that AU1 may be an important cause of slow recovery/poor prognosis under clinical situations and hence, the therapy protocol for such cases should include treatment for probable gastrointestinal bleeding.
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Background/Aims Neuroendocrine cell hyperplasia is a non-neoplastic proliferation of enterochromaffin-like cells and is considered a premalignant lesion because of their potential to progress to neuroendocrine tumor. In this study, we aimed to evaluate the demographic and clinical features, laboratory, radiological and endoscopic findings, gastric biopsy histopathological features, follow-up frequency, and histopathological findings of patients diagnosed with gastric neuroendocrine cell hyperplasia as well as to investigate the factors that play a role in the development of neuroendocrine tumors on the basis of neuroendocrine cell hyperplasia. Materials and Methods The study has been conducted in 2 centers with 282 patients that were grouped as those with and without neuroendocrine tumor. Individuals with control endoscopy were separated as those with regression of neuroendocrine cell hyperplasia and those without regression, and the determined parameters were evaluated between the groups. Results The most common histological subtype of neuroendocrine cell hyperplasia was linear + micronodular (50.4%). Neuroendocrine tumor developed in 4.3% (12/282) of the patients with neuroendocrine cell hyperplasia after a mean of 36 months. The presence of polyps as confirmed via endoscopy and dysplasia as confirmed via histopathological examination was significantly higher in favor of the group with neuroendocrine tumor (P = .01). In patients with neuroendocrine cell hyperplasia regressed and patients in whom it did not regress were examined, the rate of asymptomatic patients and increased sedimentation rate were found in favor of the group that did not regress (P = .02 and P = .02), but no difference was found in other parameters. Conclusion Neuroendocrine tumor development rate was found to be 4.3% in the background of neuroendocrine cell hyperplasia. Two factors predicting progression from neuroendocrine cell hyperplasia to neuroendocrine tumor can be elaborated as the presence of polypoid appearance due to neuroendocrine cell hyperplasia as confirmed via endoscopy and dysplasia as confirmed via histopathological examination.
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Introduction: Gastric intestinal metaplasia (GIM) is a premalignant lesion, highly associated with Helicobacter pylori infection. Previous studies have shown that H. pylori is able to induce the expression of programmed death ligand 1 (PD-L1), an inhibitory immune modulator, in gastric cells. Our aim was to investigate whether tissues from GIM patients may exploit PD-L1 expression upon H. pylori infection to evade immunosurveillance. Methods: Immunohistochemistry was performed for PD-L1 and enteroendocrine markers somatostatin and gastrin on samples derived from a cohort of patients with known GIM, both before and after H. pylori eradication. To determine the identity of any observed PD-L1-positive cells, we performed multiplex immunofluorescent staining and analysis of single-cell sequencing data. Results: GIM tissue was rarely positive for PD-L1. In normal glands from GIM patients, PD-L1 was mainly expressed by gastrin-positive G-cells. While the D-cell and G-cell compartments were both diminished 2-fold (p = .015 and p = .01, respectively) during H. pylori infection in the normal antral tissue of GIM patients, they were restored 1 year after eradication. The total number of PD-L1-positive cells was not affected by H. pylori, but the percentage of PD-L1-positive G-cells was 30% higher in infected subjects (p = .011), suggesting that these cells are preferentially rescued from destruction. Conclusions: Antral G-cells frequently express PD-L1 during homeostasis. G-cells seem to be protected from H. pylori-induced immune destruction by PD-L1 expression. GIM itself does not express PD-L1 and is unlikely to escape immunosurveillance via expression of PD-L1.
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Antibodies to different peptides produced from the gastrin precursor have been used in light microscopic- and electron microscopic-immunogo1d studies of gastrinoma tissue and normal antral mucosa. Antibodies to the C terminus of progastrin, which are known to react with the intact precursor, revealed immunoreactive material in the rough endoplasmic reticulum, Go1gi region, and electron-dense granules in gastrinoma cells. In normal antrum these antibodies again revealed the Go1gi region and a population of electron-dense granules. Other antibodies that react with the products of progastrin processing, but not the precursor, e.g., C-termina1 and N-termina1 gastrin 17 specific antibodies, revealed only granules. In addition to electron-dense granules already mentioned, the latter antibodies also revealed electron-lucent and intermediate granule populations, which in antrum were the major granule types. It is proposed that the intact precursor occurs in rough endoplasmic reticulum and Go1gi; thereafter, in the immature electron-dense granules, and subsequently in electron-lucent granules, biosynthetic processing liberates gastrin 17 and gastrin 34, which are the major active products of gastrin gene expression.
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The role of gastrin in the regulation of gastrointestinal growth and acid secretion has been addressed through recent studies involving transgenic and knockout mice. The role of gastrin as key modulator of parietal cell function and gastric acid secretion has been confirmed through studies in mice deficient in either gastrin or the gastrin/CCK-B receptor. However, although gastrin-deficient mice show no changes in gastric proliferation, they do show reduced colonic proliferation, and rates of colonic proliferation are increased in transgenic mice overexpressing glycine-extended gastrin or progastrin. This themes article highlights recent progress in our understanding of the biology of gastrin through studies in genetically modified mice.
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AIM: To develop a serum or histological marker for early discovery of gastric atrophy or intestinal metaplasia. METHODS: This study enrolled 44 patients with gastric adenocarcinoma, 52 patients with duodenal ulcer, 14 patients with gastric ulcer and 42 consecutive healthy adults as controls. Each patient received an endoscopy and five biopsy samples were obtained. The degrees of histological parameters of gastritis were categorized following the Updated Sydney System. Anti-parietal cell antibodies (APCA) and anti-Helicobacter pylori (H pylori) antibodies (AHPA) were analyzed by immunoassays. H pylori infection was diagnosed by rapid urease test and histological examination. RESULTS: Patients with gastric cancer and gastric ulcer are significantly older than healthy subjects, while also displaying higher frequency of APCA than healthy controls. Patients with positive APCA showed higher scores in gastric atrophy and intestinal metaplasia of corpus than patients with negative APCA. Patients with positive AHPA had higher scores in gastric atrophy, intestinal metaplasia, and gastric inflammation of antrum than those patients with negative AHPA. Elderly patients had greater prevalence rates of APCA. Following multivariant logistic regression analysis, the only significant risk factor for antral atrophy is positive AHPA, while that for corpus atrophy is positive APCA. CONCLUSION: The existence of positive APCA correlates with glandular atrophy in corpus and the presence of positive AHPA correlates with glandular atrophy in antrum. The existence of serum APCA and AHPA betokens glandular atrophy and requires further examination for gastric cancer.
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Oral vitamin B12 can provide an effective alternative to intramuscular injections, so giving patients a choice and reducing costs in primary care. This study investigated the effectiveness, safety, and acceptability of oral vitamin B12 as replacement therapy in patients with vitamin B12 deficiency in a city general practice population. Forty patients previously maintained on vitamin B12 injections were given 1000 μg of oral cyanocobalamin daily for up to 18 months. All the patients maintained satisfactory serum B12 levels and showed normal haematology and neurology. Compliance and acceptability was excellent. The time for a change in practice has indeed arrived.
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Pepsinogen (PG) I and PG II levels were determined in sera from 147 patients with pernicious anemia. Race, sex, age, gastrin level, and antibody status did not influence pepsinogen levels. PG I values less than 30 micrograms/L were found in 92% of cases and PG I to PG II ratios less than 3.0 in 82% of cases. At least one of these two results was abnormal in 97% of all patients with pernicious anemia. In comparison, results of other blood tests used in the investigation of pernicious anemia were less often abnormal. Serum gastrin level exceeded 200 ng/L in 90% of patients with pernicious anemia and was second to pepsinogen abnormality in diagnostic sensitivity. Results for anti-intrinsic factor antibody were positive in 73% of cases and anti-parietal cell antibody in only 52%. Although its specificity is limited, the presence of low PG I level and/or low PG I-PG II ratio is currently the most sensitive serum indicator for pernicious anemia, and absence of both can be taken as a strong argument against the diagnosis. This highly sensitive test can be combined further with the highly specific serum anti-intrinsic factor antibody test for the presumptive diagnosis of pernicious anemia when definitive tests (the Schilling test or gastric analysis for intrinsic factor) cannot be done or results are inconclusive.
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Gastric carcinoids are uncommon, and are unlike carcinoids at other gastrointestinal sites, clinically and pathologically. The authors studied specimens from 104 patients with gastric carcinoid, with study emphasis being placed on pathologic features, immunohistochemistry, clinical associations, and prognostic factors. The average age of the 47 male patients and 57 female patients was 61 years. Twenty-seven patients had chronic atrophic gastritis, 12 had pernicious anemia, and 6 had hypergastrinemia; no patient had carcinoid syndrome. Most of the tumors were confined to the mucosa and submucosa. Lymph node metastases were present in only one patient. The tumors were argyrophilic in 84% and argentaffin in 14%. Chromogranin tested positive in all patients; serotonin was detected in one-third; other hormones were much less common. Gastrin-positive tumors were antral. Of the 62 patients with follow-up, 44 were alive without disease, 4 were alive with disease, and 14 were dead (4 died of carcinoid-related disease). None of the deceased had pernicious anemia or hypergastrinemia. The tumors in patients with a fatal outcome were 2 cm or larger. Gastric carcinoids generally are indolent tumors, particularly when associated with pernicious anemia or hypergastrinemia or when smaller than 2 cm. Chromogranin is the most sensitive marker.