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Antral gastrin and somatostatin concentrations in peptic ulcer patients
Peptides, Vol. 2, Suppl. 2, pp. 281-283, 1981. Printed in the U.S.A.
Antral Gastrin and Somatostatin Concentrations in Peptic Ulcer Patients K. S U M I I , * T. F U K U S H I M A , K. H I R A T A , Y. M A T S U M O T O , E. S A N U K I , S. T S U M A R U , M. S U M I O K A , A. M I Y O S H I A N D Y. M I Y A C H I t
First and tThird Department of Internal Medicine Hiroshima University School of Medicine, Hiroshima, Japan
SUMII, K., T. FUKUSHIMA, K. HIRATA, Y. MATSUMOTO, E. SANUKI, S. TSUMARU, M. SUMIOKA, A. MIYOSHI AND Y. MIYACHL Antral gastrin and somatostatin concentrations in peptic ulcer patients. PEPTIDES 2: Suppl. 2,281-283, 1981.--As an attempt to approach the pathogenesis of peptic ulcer disease, antral gastrin and somatostatin concentrations were studied in normal subjects, patients with duodenal ulcer and gastric ulcer. In the patients with peptic ulcer, antral somatostatin concentrations were significantly lower than those in normal subjects. In non-ulcer subjects, including normal subjects and patients with atrophic gastritis, antral somatostatin concentrations were correlated inversely with the degree of antral gastritis, while in the patients with peptic ulcer, especially in duodenal ulcer, they were low, irrespective of histological picture of antral mucosa. In the patients with duodenal ulcer, low antral somatostatin concentrations with high antral gastrin/somatostatin ratio may cause increased serum gastrin levels and increased gastric acid secretion. From the above findings, it has been concluded that low antral somatostatin levels may be related to the pathogenesis of duodenal ulcer disease.
Gastritis
Atrophic gastritis
Gastric acid secretion
ALTHOUGH the etiology of peptic ulcer is not yet defined, an important role for gastrin has been accepted [5]. Recently somatostatin has been shown to exert an inhibitory effect on the release of gastrin from gastric antrum [1]. There is little information concerning the level of somatostatin in gastrointestinal tissues from patients with peptic ulcer. In the present study we measured both gastrin and somatostatin concentrations in endoscopically obtained biopsy specimens and correlated them with serum gastrin, gastric acid secretion and histological findings. METHOD
Forty-four patients with duodenal ulcer (40.3-+ 1.8 years of age), 32 patients with gastric ulcer (54.1 -+2.4 years of age) and 36 normal subjects without endoscopically macroscopic lesions of gastric mucosa (30.7___2.3 years of age) were studied. After an overnight fast, biopsy specimens were obtained endoscopically using Olympus gastroduodenoscopes. Six to eight specimens, each of which was approximately 4 mg in weight, were taken from the lesser curvature of the antrum and anterior wall of the midcorpus. Three of these specimens were used for the determination of somatostatin and gastrin, and one or two for histological examination. Three biopsy specimens were extracted with either 2 N acetic acid or boiling water. After centrifugation, the supernatant was lyophilized and resuspended in 2 ml of 0.01 M pH 7.4 phosphate buffer saline containing 0.5% bovine serum albumin. Somatostatin antiserum was produced by immunizing rabbits with synthetic somatostatin- bovine serum albumin
Serum gastrin
Somatostatin
conjugate prepared by carbodiimide method. The antiserum did not cross react with gastrin, secretin, insulin, glucagon, caerulein and substance P. Tyrl-somatostatin was iodinated by lactoperoxidase method, subsequently purified on Sephadex G50 gel chromatography. Elution was performed with 0.1 N acetic acid containing 0.25% bovine serum albumin. The separation of free from antibody bound nSI-Tyr~somatostatin was performed with dextran coated charcoal. The sensitivity of the assay was 3 pg/tube and intraassay and interassay variation were 6.8% and 13.7%, respectively. The gastrin levels in the serum and tissue extracts were determined by a specific radioimmunoassay described previously [4]. All samples were radioimmunoassayed in duplicate at two different dilutions. Gastric acid secretion test was performed as follows: after an overnight fast, the gastric juice was collected for 1 hour for the determination of basal acid output (BAO), and after tetragastrin (4 /~g/kg body weight) was injected intramuscularly, the gastric juice was collected every 10 minutes for one hour for the determination of maximal acid output (MAO). RESULTS
In normal subjects, the concentrations of antral gastrin and somatostatin were 6.68-+0.63 ng/mg and 2.10-+0.23 ng/mg, respectively, with the gastrin and somatostatin ratio (G/S ratio) of 4.02-+0.44. In normal subjects with normal histological findings and normal gastric acid output, good correlation existed between gastrin and somatostatin concentrations in the gastric antrum (r=0.6324) (Fig. 1), while in
Copyright © 1981 A N K H O International Inc.--0196-9781/81/060281-03500.80/0
282
SUMII ET AL°
..p<0.O01 • p
~16
iv
I
r : 0J532/. (n=32)
,~
I
II
I
I
¢::: 2" .< I
I
I
I
I
O
1
2
3
4
5
tn
Antral Somatostatin (ng/mg)
--~ C
FIG. 1. Correlation between antral gastrin and somatostatin concentrations in normal subjects.
Non-Ulcer n:46
c
o
n:36
DU
GU
n=44
n=32
FIG. 2. Antra] somatostatin concentrations in normal subjects, and in patients with duodenal and gastric ulcer. ~°
2
o N o n - U l c e r . n=32
$
z:
:
t0 Grade of Atrophic Gastritis
Nn
Normal
GU n:24
4
3 U3
DU n : 35
1
=
i7
:" 1: :
:
:
A0,1A2 A3
:
.. .
;°
.~L
v
*."
E r :
:
:
:
Ao.1A2 A3
:
:
',
o 0 0
:
A0,1A2 A3
0 0
0
83
o
o o
AO,1; mild atrophic gastritis(Antrum) A 2 ; moderate atrophic gastritis(Antrum) A3; severe atrophic gastritis(Antrum}
o
o°
o
0 0 0
•
o
o
°5.;:: Oo
°0% ~-.
o o FIG. 3. Antral somatostatin concentrations grouped according to histological picture of antral mucosa in non-ulcer subjects, and in patients with duodenal and gastric ulcer. Non-ulcer subjects means normal subjects plus the patients with atrophic gastritis.
n=32
• DU,
.c_ 4
" :
~ E5
oO
•
1
~)
e
•o ~ •
... , •
°
~•
' , 20 30 40 M a x i m a l Acid O u t p u t ( m E q l h )
FIG. 4. Correlation between antral somatostatin concentrations and maximal acid output (MAO) in non-ulcer subjects and in patients with duodenal ulcer. subjects with atrophic gastritis, gastric ulcer and duodenal ulcer, no correlation existed (data not shown). Thus gastric antrum, under physiological conditions, seems to be capable of producing gastrin and somatostatin in parallel, and disruption of the physiological relationship between these two peptides appears to occur in damaged tissues. The concentrations of somatostatin in the gastric antrum of the patients with duodenal ulcer and gastric ulcer were 0.56-+0.06 ng/mg and 0.38-+0.07 ng/mg, respectively, which were less than 30% of that in normal subjects (Fig. 2). When antral somatostatin levels were compared with histological appearance, there were marked differences in
non-ulcer subjects (which includes normal subjects and patients with atrophic gastritis) and patients with duodenal ulcer and gastric ulcer. The more severe the atrophic changes of antrum (A-0-A-3), the lower the levels of somatostatin in non-ulcer subjects, while in patients with peptic ulcer the antral somatostatin concentrations were very low regardless of the degree of atrophic changes. The levels of the antral somatostatin in non-ulcer subjects with severe atrophic gastritis was as low as those in patients with ulcer (Fig. 3).
ANTRAL GASTRIN/SOMATOSTATIN IN ULCER
283
• ..p
o
"o
40 t
I
I
'-r
.c_ 20
...
[
--
]l
"
I
o'--
20
loo
..-p<0.001
.p
I! I
I
T
2o]
1"
..T_ U3L9 e-
1" t-
<
!1 Normal D U n=31 n=33
GU n=29
II I
n
Normal D U ( MAO>20 ) n=21 n=15
FIG. 5. Antra] gastrirdsomatostatin ratio in normal subjects and in patients with duodenal and gastric ulcer.
FIG. 6. Antral gastrin/somatostatin ratio, serum gastrin levels and maximal acid output in duodenal ulcer patients with MAO above 20 mEq/hr. In non-ulcer subjects, antra] somatostatin seemed to correlate with maximal acid output, while in patients with duodenal ulcer the antral somatostatin remained low irrespective o f maximal acid output (Fig. 4). Antral G/S ratio in normal subjects was 4.02-+0.44, compared with 14.56-+1.52 and 9.89-+1.26 in patients with duodenal ulcer and gastric ulcer (Fig. 5). In duodenal ulcer subjects the elevated serum gastrin with high antral G/S ratio was accompanied by high gastric acid secretion (Fig. 6). DISCUSSION The present study has demonstrated that antral somatostatin concentrations are low in patients with peptic ulcers, especially those with duodenal ulcers. Somatostatin, which inhibits the secretion of growth hormone, is also a potent inhibitor of gastrin release induced by exogenous stimmulants such as foods [2]. Immunohistological studies have shown that somatostatin cells of gastric mucosa possess long cytoplamic processes that contact gastrin cells, suggesting a
local regulatory function for somatostatin on gastrin release [3]. We previously reported [4] high concentrations ofgastrin in the antrum and exaggerated gastrin response to test meals in patients with duodenal ulcer. The low antral somatostatin levels with slightly elevated gastrin concentrations in patients with duodenal ulcer resulted in markedly elevated G/S ratio. This high G/S ratio in the antrum may be an important factor in the increased gastrin release and high gastric acid secretion observed in patients with duodenal ulcer. In non-ulcer subjects, antral somatostatin concentration was inversely correlated with degree of inflammation. However, in duodenal ulcer patients, antra] somatostatin was low irrespective of the histological picture. Marked reduction in antral somatostatin with high G/S ratio may be specific for duodenal ulcer disease. Further studies are necessary to clarify the rate of the synthesis and metabolism of somatostatin in the tissues of duodenal ulcer patients.
REFERENCES 1. Bloom, S. R., C. H. Mortimer, M. O. Thorner, G. M. Besser, R. Hall, A. Gomez-Pan, U. M. Roy, R. C. G. Russel, D. H. Coy, A. J. Kastin and A. V. Shally. Inhibition of gastrin and gastric acid secretion by growth hormone releasing-inhibiting hormone. Lancet 2: 1106-1109, 1974. 2. Konturek, S. J., J. Swierczek, N. Kwiecien, E. Mikos, J. Oleksy and Z. Wierzbicki. Effect of somatostatin on meal-induced gastric secretion in duodenal ulcer patients. Am. J. dig. Dis. 22: 981-989, 1978.
3. Larsson, L. I., N. Goltermann, L. deMagistris, J. F. Rehfeld and T. W. Schwartz. Gastric somatostatin cells: Morphological substrate for local (paracrine) functions. Science 205: 1393--1394, 1979.
4. Sumii, K., Y. Yokoyama, Y. Matsui, N. Kikkawa, T. Hidaka, K. Suenaga, K. Ohe and A. Miyoshi. The increased antra/gastrin content and its release in response to test meal in patients with duodenal ulcer. Hiroshima J. reed. Sci. 28: 221-227, 1979. 5. Walsh, J. H. Pathogenetic role of gastrins. In: Gastrin and the Vagus. edited by J. F. Rehfeld and E. Amdrup. London: Academic Press, 1979, pp. 181-198.
Antral Gastrin and Somatostatin Concentrations in Peptic Ulcer Patients K. S U M I I , * T. F U K U S H I M A , K. H I R A T A , Y. M A T S U M O T O , E. S A N U K I , S. T S U M A R U , M. S U M I O K A , A. M I Y O S H I A N D Y. M I Y A C H I t
First and tThird Department of Internal Medicine Hiroshima University School of Medicine, Hiroshima, Japan
SUMII, K., T. FUKUSHIMA, K. HIRATA, Y. MATSUMOTO, E. SANUKI, S. TSUMARU, M. SUMIOKA, A. MIYOSHI AND Y. MIYACHL Antral gastrin and somatostatin concentrations in peptic ulcer patients. PEPTIDES 2: Suppl. 2,281-283, 1981.--As an attempt to approach the pathogenesis of peptic ulcer disease, antral gastrin and somatostatin concentrations were studied in normal subjects, patients with duodenal ulcer and gastric ulcer. In the patients with peptic ulcer, antral somatostatin concentrations were significantly lower than those in normal subjects. In non-ulcer subjects, including normal subjects and patients with atrophic gastritis, antral somatostatin concentrations were correlated inversely with the degree of antral gastritis, while in the patients with peptic ulcer, especially in duodenal ulcer, they were low, irrespective of histological picture of antral mucosa. In the patients with duodenal ulcer, low antral somatostatin concentrations with high antral gastrin/somatostatin ratio may cause increased serum gastrin levels and increased gastric acid secretion. From the above findings, it has been concluded that low antral somatostatin levels may be related to the pathogenesis of duodenal ulcer disease.
Gastritis
Atrophic gastritis
Gastric acid secretion
ALTHOUGH the etiology of peptic ulcer is not yet defined, an important role for gastrin has been accepted [5]. Recently somatostatin has been shown to exert an inhibitory effect on the release of gastrin from gastric antrum [1]. There is little information concerning the level of somatostatin in gastrointestinal tissues from patients with peptic ulcer. In the present study we measured both gastrin and somatostatin concentrations in endoscopically obtained biopsy specimens and correlated them with serum gastrin, gastric acid secretion and histological findings. METHOD
Forty-four patients with duodenal ulcer (40.3-+ 1.8 years of age), 32 patients with gastric ulcer (54.1 -+2.4 years of age) and 36 normal subjects without endoscopically macroscopic lesions of gastric mucosa (30.7___2.3 years of age) were studied. After an overnight fast, biopsy specimens were obtained endoscopically using Olympus gastroduodenoscopes. Six to eight specimens, each of which was approximately 4 mg in weight, were taken from the lesser curvature of the antrum and anterior wall of the midcorpus. Three of these specimens were used for the determination of somatostatin and gastrin, and one or two for histological examination. Three biopsy specimens were extracted with either 2 N acetic acid or boiling water. After centrifugation, the supernatant was lyophilized and resuspended in 2 ml of 0.01 M pH 7.4 phosphate buffer saline containing 0.5% bovine serum albumin. Somatostatin antiserum was produced by immunizing rabbits with synthetic somatostatin- bovine serum albumin
Serum gastrin
Somatostatin
conjugate prepared by carbodiimide method. The antiserum did not cross react with gastrin, secretin, insulin, glucagon, caerulein and substance P. Tyrl-somatostatin was iodinated by lactoperoxidase method, subsequently purified on Sephadex G50 gel chromatography. Elution was performed with 0.1 N acetic acid containing 0.25% bovine serum albumin. The separation of free from antibody bound nSI-Tyr~somatostatin was performed with dextran coated charcoal. The sensitivity of the assay was 3 pg/tube and intraassay and interassay variation were 6.8% and 13.7%, respectively. The gastrin levels in the serum and tissue extracts were determined by a specific radioimmunoassay described previously [4]. All samples were radioimmunoassayed in duplicate at two different dilutions. Gastric acid secretion test was performed as follows: after an overnight fast, the gastric juice was collected for 1 hour for the determination of basal acid output (BAO), and after tetragastrin (4 /~g/kg body weight) was injected intramuscularly, the gastric juice was collected every 10 minutes for one hour for the determination of maximal acid output (MAO). RESULTS
In normal subjects, the concentrations of antral gastrin and somatostatin were 6.68-+0.63 ng/mg and 2.10-+0.23 ng/mg, respectively, with the gastrin and somatostatin ratio (G/S ratio) of 4.02-+0.44. In normal subjects with normal histological findings and normal gastric acid output, good correlation existed between gastrin and somatostatin concentrations in the gastric antrum (r=0.6324) (Fig. 1), while in
Copyright © 1981 A N K H O International Inc.--0196-9781/81/060281-03500.80/0
282
SUMII ET AL°
..p<0.O01 • p
~16
iv
I
r : 0J532/. (n=32)
,~
I
II
I
I
¢::: 2" .< I
I
I
I
I
O
1
2
3
4
5
tn
Antral Somatostatin (ng/mg)
--~ C
FIG. 1. Correlation between antral gastrin and somatostatin concentrations in normal subjects.
Non-Ulcer n:46
c
o
n:36
DU
GU
n=44
n=32
FIG. 2. Antra] somatostatin concentrations in normal subjects, and in patients with duodenal and gastric ulcer. ~°
2
o N o n - U l c e r . n=32
$
z:
:
t0 Grade of Atrophic Gastritis
Nn
Normal
GU n:24
4
3 U3
DU n : 35
1
=
i7
:" 1: :
:
:
A0,1A2 A3
:
.. .
;°
.~L
v
*."
E r :
:
:
:
Ao.1A2 A3
:
:
',
o 0 0
:
A0,1A2 A3
0 0
0
83
o
o o
AO,1; mild atrophic gastritis(Antrum) A 2 ; moderate atrophic gastritis(Antrum) A3; severe atrophic gastritis(Antrum}
o
o°
o
0 0 0
•
o
o
°5.;:: Oo
°0% ~-.
o o FIG. 3. Antral somatostatin concentrations grouped according to histological picture of antral mucosa in non-ulcer subjects, and in patients with duodenal and gastric ulcer. Non-ulcer subjects means normal subjects plus the patients with atrophic gastritis.
n=32
• DU,
.c_ 4
" :
~ E5
oO
•
1
~)
e
•o ~ •
... , •
°
~•
' , 20 30 40 M a x i m a l Acid O u t p u t ( m E q l h )
FIG. 4. Correlation between antral somatostatin concentrations and maximal acid output (MAO) in non-ulcer subjects and in patients with duodenal ulcer. subjects with atrophic gastritis, gastric ulcer and duodenal ulcer, no correlation existed (data not shown). Thus gastric antrum, under physiological conditions, seems to be capable of producing gastrin and somatostatin in parallel, and disruption of the physiological relationship between these two peptides appears to occur in damaged tissues. The concentrations of somatostatin in the gastric antrum of the patients with duodenal ulcer and gastric ulcer were 0.56-+0.06 ng/mg and 0.38-+0.07 ng/mg, respectively, which were less than 30% of that in normal subjects (Fig. 2). When antral somatostatin levels were compared with histological appearance, there were marked differences in
non-ulcer subjects (which includes normal subjects and patients with atrophic gastritis) and patients with duodenal ulcer and gastric ulcer. The more severe the atrophic changes of antrum (A-0-A-3), the lower the levels of somatostatin in non-ulcer subjects, while in patients with peptic ulcer the antral somatostatin concentrations were very low regardless of the degree of atrophic changes. The levels of the antral somatostatin in non-ulcer subjects with severe atrophic gastritis was as low as those in patients with ulcer (Fig. 3).
ANTRAL GASTRIN/SOMATOSTATIN IN ULCER
283
• ..p
o
"o
40 t
I
I
'-r
.c_ 20
...
[
--
]l
"
I
o'--
20
loo
..-p<0.001
.p
I! I
I
T
2o]
1"
..T_ U3L9 e-
1" t-
<
!1 Normal D U n=31 n=33
GU n=29
II I
n
Normal D U ( MAO>20 ) n=21 n=15
FIG. 5. Antra] gastrirdsomatostatin ratio in normal subjects and in patients with duodenal and gastric ulcer.
FIG. 6. Antral gastrin/somatostatin ratio, serum gastrin levels and maximal acid output in duodenal ulcer patients with MAO above 20 mEq/hr. In non-ulcer subjects, antra] somatostatin seemed to correlate with maximal acid output, while in patients with duodenal ulcer the antral somatostatin remained low irrespective o f maximal acid output (Fig. 4). Antral G/S ratio in normal subjects was 4.02-+0.44, compared with 14.56-+1.52 and 9.89-+1.26 in patients with duodenal ulcer and gastric ulcer (Fig. 5). In duodenal ulcer subjects the elevated serum gastrin with high antral G/S ratio was accompanied by high gastric acid secretion (Fig. 6). DISCUSSION The present study has demonstrated that antral somatostatin concentrations are low in patients with peptic ulcers, especially those with duodenal ulcers. Somatostatin, which inhibits the secretion of growth hormone, is also a potent inhibitor of gastrin release induced by exogenous stimmulants such as foods [2]. Immunohistological studies have shown that somatostatin cells of gastric mucosa possess long cytoplamic processes that contact gastrin cells, suggesting a
local regulatory function for somatostatin on gastrin release [3]. We previously reported [4] high concentrations ofgastrin in the antrum and exaggerated gastrin response to test meals in patients with duodenal ulcer. The low antral somatostatin levels with slightly elevated gastrin concentrations in patients with duodenal ulcer resulted in markedly elevated G/S ratio. This high G/S ratio in the antrum may be an important factor in the increased gastrin release and high gastric acid secretion observed in patients with duodenal ulcer. In non-ulcer subjects, antral somatostatin concentration was inversely correlated with degree of inflammation. However, in duodenal ulcer patients, antra] somatostatin was low irrespective of the histological picture. Marked reduction in antral somatostatin with high G/S ratio may be specific for duodenal ulcer disease. Further studies are necessary to clarify the rate of the synthesis and metabolism of somatostatin in the tissues of duodenal ulcer patients.
REFERENCES 1. Bloom, S. R., C. H. Mortimer, M. O. Thorner, G. M. Besser, R. Hall, A. Gomez-Pan, U. M. Roy, R. C. G. Russel, D. H. Coy, A. J. Kastin and A. V. Shally. Inhibition of gastrin and gastric acid secretion by growth hormone releasing-inhibiting hormone. Lancet 2: 1106-1109, 1974. 2. Konturek, S. J., J. Swierczek, N. Kwiecien, E. Mikos, J. Oleksy and Z. Wierzbicki. Effect of somatostatin on meal-induced gastric secretion in duodenal ulcer patients. Am. J. dig. Dis. 22: 981-989, 1978.
3. Larsson, L. I., N. Goltermann, L. deMagistris, J. F. Rehfeld and T. W. Schwartz. Gastric somatostatin cells: Morphological substrate for local (paracrine) functions. Science 205: 1393--1394, 1979.
4. Sumii, K., Y. Yokoyama, Y. Matsui, N. Kikkawa, T. Hidaka, K. Suenaga, K. Ohe and A. Miyoshi. The increased antra/gastrin content and its release in response to test meal in patients with duodenal ulcer. Hiroshima J. reed. Sci. 28: 221-227, 1979. 5. Walsh, J. H. Pathogenetic role of gastrins. In: Gastrin and the Vagus. edited by J. F. Rehfeld and E. Amdrup. London: Academic Press, 1979, pp. 181-198.