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Inhibition of gastrin release and gastric secretion by calcitonin in patients with peptic ulcer
Inhibition of Gastrin Release and Gastric Secretion by Calcitonin in Patients with Peptic Ulcer Horst D. Becker, MD, Galveston,
Texas
David D. Reeder, MD, Galveston,
Texas
Murphy T. Scurry, MD, Galveston,
Texas
James C. Thompson, MD, Galveston,
Texas
The relationship between calcium metabolism and gastric secretion has become of increasing interest, since it has been shown that induced hypercalcemia causes an increase in gastric secretion by stimulating the release of gastrin [I]. Calcitonin has been shown to be a potent inhibitor of basal or pentagastrin-stimulated gastric secretion in man [2]. The mechanism by which calcitonin exerts this inhibitory action is not known. The present studies were undertaken to determine the effect of intravenous calcitonin on basal levels of serum gastrin, measured by radioimmuhuman noassay, in normal and hypercalcemic subjects. We further studied the effect of calcitonin on the serum gastrin response to food in normal subjects. Material and Methods Studies were performed on the following human volunteers: eight normal subjects, six patients with duodenal ulcer (DU) disease, three patients with primary hyperparathyroidism (HPT), six patients with histologically proved Zollinger-Ellison (Z-E) syndrome, and From the Departments of Surgery and Internal Medicine, The University of Texas Medical Branch, Galveston, Texas. This work was supported by grants from the National Institutes of Health (AM 15241) and General Clinical Research Centers Branch (DHEW Grant RR 00073) and bv a arant from The John A. Hartford Foundation, Inc. Repiint re&e& should be addressed to Dr Thompson, Oepartinent of Surgery, The University of Texas Medical Branch, Galveston, Texas 77550. Presented at the Fourteenth Annual Meeting of the Society for Surgery of the Alimentary Tract, New York, New York, May 22 and 23, 1973.
Volume 127, January 1974
three patients who had both the Z-E syndrome and HPT (ZE + HPT). The six patients with the Z-E syndrome had had either subtotal or total gastrectomy and had residual tumor as indicated by persistently high levels of serum gastrin. After an overnight fast, patients were given an intravenous infusion of synthetic salmon calcitonin (Ar-2077 calcitonin; Armour Pharmaceutical Co) at a rate of 2 MRCU/kg/hour. Additionally, each patient received 2 MRCIJ/kg as an intravenouszloading dose over the first fifteen minutes of t’he experiment. Effect of Calcitonin on Basal Levels of Serum Gastrin, Serum
Calcium,
and Gastric
Secretion.
Initial
studies were performed in eight normal adult subjects without evidence of gastrointestinal disease. Two blood samples for serum gastrin and calcium determinations were obtained after which the subjects received a ninety minute infusion of calcitonin. Further blood samples were obtained at intervals for 150 minutes after the initiation of the calcitonin infusion. In three of the normal subjects, gastric secretions were aspirated continuously via a sump type nasogastric tube throughout the study, and thirty minute acid outputs were determined. Similar studies were performed in six DU patients, three patients with HPT, six Z-E patients, and three patients with ZE + HPT. The protocol differed slightly in that the calcitonin infusion lasted two hours and the sampling period was for three and a half hours after initiation of the calcitonin infusion. Gastric acid output was measured throughout the studies in all patients except the Z-E patients who had undergone gastrectomy. Effect of Calcitonin on Food-Stimulated Levels of Serum Gastrin in Normal Subjects. In six normal
subjects
paired test-control
studies
were performed
on
71
Becker et al
two different days; the sequence was alternated randomly. In the control study, two basal samples for serum gastrin measurement were obtained after which the patient drank a 500 ml liquid meal containing 52 gm of protein, 7 gm of fat, and 150 gm of carbohydrate. Blood samples were obtained at intervals for 150 minutes. In the test study, this protocol was repeated and, in addition, an intravenous infusion of calcitonin was given over the first sixty minutes after eating. Serum gastrin concentrations in these studies were measured by radioimmunoassay [3]. The antigastrin antibodies currently in use in our laboratory were raised in rabbits using a method described by Vaitukaitis et al [4]; 50 pg of synthetic human gastrin I (amino acid residues 2-17), conjugated to bovine serum albumin, was injected intracutaneously at thirty to fifty sites on the back. In addition, each rabbit was given 0.5 ml of crude pertussis vaccine (Eli Lilly and Co) subcutaneously. Forty days after the initial immunization, the rabbits received a booster injection containing 20 Hg of antigen. Antigastrin antibodies of sufficient system titer for use in the radioimmunoassay (l:lOO,OOO final dilution) were present three months after the initial immunization. Serum gastrin concentrations are expressed as picograms per milliliter (pg/ ml) or as the integrated gastrin response [5] over a given period of time, expressed as nanogram minutes per milliliter (ng-min/ml). Serum calcium concentrations were determined by atomic absorption using the model 303 Perkin-Elmer spectrophotometer. Gastric acid output was determined by titration of a 1 ml sample with 0.1 N NaOH (phenol red used as indicator). Results are expressed as mean values with corresponding standard errors (&SE). The Student t test was used to analyze the significance of differences between means. Statistically significant differences were considered to be those with p values less than 0.05. Results Effect of Calcitonin on Basal Levels of Serum Gastrin, Serum Calcium, and Gastric Secretion. 1. In normal man: In the five normal subjects who were studied without nasogastric intubation, basal serum gastrin concentration was 65 f 2 pg/ml and did not change significantly during the ninety minute calcitonin infusion. (Figure 1.) Basal serum calcium levels of 9.4 f 0.5 mg/lOO ml decreased slightly to 8.9 f 0.2 mg/lOO ml sixty minutes after initiation of the calcitonin infusion. In the three normal subjects in whom gastric acid output was measured, basal serum gastrin levels of 103 f 4 pg/ml and basal serum calcium levels of 8.8 f 0.4 mg/lOO ml were not significantly changed by the calcitonin infusion. Basal gastric acid output was 1.08 f 0.42 mEq per thirty minutes; secretion was completely suppressed in each
72
subject within thirty minutes after initiation of the infusion. 2. In patients with duodenal ulcer (Figure 2): The mean basal serum gastrin concentration in six DU patients was 113 f 9 pg/ml. The mean basal concentration of serum gastrin in the control group of eight normal subjects was 79 f 5 pg/ml; this difference in gastrin values was signficant (p cO.05). After ninety minutes of calcitonin infusion, serum gastrin in the DU patients had fallen to 92 f 6 pg/ml (p X0.05). Serum calcium decreased significantly from a basal value of 8.8 f 0.3 mg/lOO ml to 8.0 f 0.2 mg/lOO ml by sixty minutes after the calcitonin infusion was stopped. The mean basal gastric acid output was 1.27 f 0.29 mEq per thirty minutes, which was inhibited strongly during calcitonin infusion to a low value of 0.05 f 0.04 mEq per thirty minutes (p cO.01). By ninety minutes afier the infusion was stopped, gastric secretion had risen to 0.86 f 0.56 mEq per thirty minutes. 3. In patients with hyperparathyroidism (Figure 3): Mean basal serum gastrin concentration of 157 f 20 pg/ml decreased during calcitonin infusion to 107 f 15 pg/ml at 120 minutes. This decrease in gastrin paralleled a decrease in serum calcium (from 10.9 f 0.7 mg/lOO ml to 9.1 f 0.4 mg/lOO ml). The basal gastric acid output was 1.89 f 0.75 mEq per thirty minutes, which was strongly depressed by calcitonin. (Figure 3.) 4. In patients with Zollinger-Ellison tumors (Figure 4): The mean basal gastrin concentration was 1,498 f 697 pg/ml. During calcitonin infusion serum gastrin decreased to 833 f 506 pg/ml (p cO.05). Serum calcium did not change significantly throughout the experiment. 5. In patients with Zollinger-Ellison tumors and hyperparathyroidism (Figure 5): The mean basal gastrin concentration was 703 f 129 pg/ml, which decreased during calcitonin infusion to 524 f 188 pg/ml at sixty minutes. Serum calcium fell from 10.7 f 0.3 to 9.4 f 0.3 mg/lOO ml. The basal gastric acid output in these three patients was 9.82 f 4.82 mEq per thirty minutes and was abolished by the calcitonin infusion. Effect of Calcitonin on Food-Stimulated Levels of Serum Gastrin in Normal Man (Figure 6). The mean basal serum gastrin concentration in the six normal subjects was 85 f 8 pg/ml on the control day and 76 f 8 pg/ml on the test day. Calcitonin infusion almost totally abolished the serum gastrin response to food. The integrated gastrin output for the 150 minute test period was 2.97 f 1.34 ng-min/ml on the control day and -0.19 f 0.18 ng-min/ml on the test day.
The American Journal of Surgery
Calcitonln
in Gastrin
Release
and bstric
Secretion
5 NORMAL SUBJECTS
!
7:
GASTRIN pg/mi
5” ‘/
,oo,i”\t\. GASTRIN
r-i--_
--_;+--.~”
,ic
pg/mf 75.
__.... --___._ ______. *--- .---.__ _____*____\ Serum C0iCl”rn
0’ CALCIUM ‘90 mq/Kxh
,oo CALCIUM
mg/100mi .80 -60
*---- -_.. ___ . . . ..__ -.----.----.____
50
:
.. serum COlC,“rn
..I:.
<
20 .li
‘10
I/(
1
.__
30
‘80 H’
mEq/30mln
60 MINUTES
Figure 1. Effect of calcitonin on basal levels of serum gastrin and calcium in normal man.
Figure 2. Effect of calcitonin on basal levels of serum gastrin and calcium and on gastric acid output in patients with duodenal ulcer. The asterisk indicates the serum gastrin value to be significantly lower than basal values (p CO. 05).
GASTRIN pghi
LB0
H+ mEq/ 3Omtn
MINUTES
Figure 3. Effect of calcitonin on basal levels of serum gastrin and calcium and on gastric acid output in three patients with primary hyperparathyroidism.
Figure 4. Effect of calcitonin on basal levels of serum gastrin and calcium in patients with the Zollinger-Ellison syndrome who had had gastrectomy. Asterisks identify values significantly lower than basal (p X0.05).
3 PATIENTS
I HYPERPARATHYROIDISM
6 NORMAL
t Z - E SYNDROME
SUBJECTS
1
GASTRIN Pg/ml
Figure 5. Effect of calcitonin on basal levels of serum gastrin and calcium and on gastric acid output in patients who had both hyperparathyroidism and the Zollinger-Ellison syndrome.
Volume
127,
January
1974
Figure 6. Effect of calcitonin on food-stimulated gastrin levels in normal man.
serum
73
Becker et al
Comments
It has been demonstrated that calcitonin has an inhibitory effect on basal or stimulated gastric secretion and on pancreatic secretion in man [Z]. Our results show that calcitonin is a strong inhibitor of basal gastric secretion in normal man and in patients with duodenal ulcer disease, hyperparathyroidism, or Zollinger-Ellison syndrome. The mechanisms of inhibition are still not well understood. The results of the present study show that calcitonin depresses basal levels of serum gastrin in patients who have elevated concentrations of serum gastrin (patients with duodenal ulcer, hyperparathyroidism, and the Zollinger-Ellison syndrome). In normal subjects, however, calcitonin decreases basal gastric secretion strongly without changing basal serum gastrin levels. The results thus provide evidence that calcitonin inhibits gastric secretion by two separate mechanisms. First, calcitonin apparently acts directly at the parietal cell, and second, it decreases elevated levels of serum gastrin. This decrease in serum gastrin concentration could be explained either by depression of the release of gastrin or by activation of catabolic mechanisms; our studies do not allow a choice between these two possibilities. Gastrin is known to exist in at least three molecular sizes. The originally described form had 17-amino acids with a molecular weight of about 2100 [6]. Yalow and Berson [7,8] have shown that there is a larger form of gastrin with a molecular weight of around 7000 which predominates in the circulation. This larger form has 34-amino acids [9] and appears to be increased in circulating plasma after a meal [S]. A possible explanation for the action of calcitonin is that it has differential effects on the release (or catabolic) mechanisms affecting the different forms of gastrin. Previous studies from our laboratory have shown that in patients with duodenal ulcer, secretin [5] and glucagon [IO] have effects on gastric secretion and gastrin that are similar to those of calcitonin. There is a difference, however, in that both secretin and glucagon may suppress basal levels of gastrin in normal subjects and elevate levels of gastrin in patients with the Zollinger-Ellison syndrome. Glucagon caused a decrease in levels of serum calcium; secretin did not [9]. There have been many recent studies on the relation between gastrointestinal hormones and the secretion of calcitonin. It has been shown that glucagon [11], cholecystokinin (CCK) [12-141, the
74
C-terminal octapeptide of CCK [12], caerulein [12], pentagastrin [12,15-181, pure porcine gastrin II [14], and synthetic human gastrin I [14] are stimulants for the release of calcitonin from the thyroid of pigs. Care and co-workers [11-14,161 showed that endogenous gastrin caused a significant release of calcitonin in pigs. Furthermore, Phillippo and associates [18] found an immediate increase of calcitonin in sheep after food intake. Go and co-workers [19] reported high serum calcitonin levels in patients with Zollinger-Ellison tumors and low serum gastrin levels in patients with medullary carcinoma of the thyroid. In recent studies we have found that calcitonin depresses calcium-induced hypergastrinemia in cats (201. These results lead to the speculation that calcitonin may have a regulatory function in the release and catabolism of the gastrointestinal hormones. The present studies show that dalcitonin depresses serum calcium levels significantly in patients with hypercalcemia and only slightly depresses serum calcium in persons with normal values. These findings provide evidence that the depression of serum gastrin and of gastric secretion by calcitonin is independent of the serum calcium levels. Tenenhouse, Rasmussen, and Nagata [21] postulated that calcitonin acts by altering cellular calcium exchange by a direct activation of the calcium pump. That could explain our findings in cats [20], in which calcitonin strongly inhibited pentagastrinand histamine-stimulated gastric secretion. Summary We studied the effect of an intravenous infusion of calcitonin (2 MRCU/kg) on gastric secretion and serum gastrin and serum calcium levels in eight normal subjects, six patients with duodenal ulcer disease, three patients with primary hyperparathyroidism, six patients with histologically proved Zollinger-Ellison syndrome, and three patients with the Zollinger-Ellison syndrome and hyperparathyroidism. Gastric secretion was greatly inhibited in all groups of patients. Serum calcium was significantly diminished only in patients with hypercalcemia. Serum gastrin levels were depressed in all patients with elevated basal gastrin levels (DU, HPT, Z-E, and ZE + HPT). In normal subjects calcitonin inhibited strongly the serum gastrin response to food. These findings suggest that calcitonin may have a regulatory function in the release or catabolism of the hormone gastrin.
The American Journal of Surgery
Calcitonin
References
the adenyl docrinol48:
1. Reeder DD. Jackson BM, Ban J, Clendinnen BG, Davidson WD. Thompson JC: Influence of hypercalcemia on gastric secretion and serum gastrin concentrations in man Ann Surg 172: 540, 1970 2. Hesch RD. Hufnel N, Schmidt H, Winkler K. Hasenjager M. Paschen K. Becker HD, Fuchs K, Creutzfeldt W: Gastrointestinal effects of calcitonin in man, p 94. Gastrointestinal Hormones (Demling L, ed). Stuttgart, Thieme Verlag, 1972. 3. Jackson BM. Reeder DD, Thompson JC: Dynamic characteristicc of qastrin release. Am J Surg 123: 137, 1972. 4. Vaitukaitis J. Robbins JB. Nieschlag E, Rose GT: A method for producing specific antisera with small doses of immunogen. J C/in Endocrinol Mefab 33: 988, 1971. 5. Thompson JC. Reeder DD, Bunchman HH, Becker HD. Brandt EN Jr: Effect of secretin on circulating gastrin. Ann Surg 176: 384, 1972. 6. Gregory RA. Tracy HJ: The constitution and properties of two gastrlns extracted from hog antral mucosa. Gut 5: 103, 1964 7. Yallow RS. Berson SA: Size and charge distinctions between human plasma gastrin in peripheral blood and heptadecapeptide gastrins. Gastroenterology 58: 609, 1970.
Yalow RS, Berson SA: Further studies on the nature of immunoreactive gastrin in human plasma. Gastroenterology 60: 203. 1971. 9. Gregory RA. Tracy HJ: Isolation of two “big gastrins” from Zollinaer-Ellison tumour tissue. Lancet 2: 797. 8.
1972.
-
10. Becker HD. Reeder DD, Thompson JC: The effect of glucagon on circulating gastrin. Gastroenterology 65: 28, 1973. 11. Care AD, Bates RFL, Gitelman HI: A possible role for
Volume
127,
January
1974
12
13.
14.
15.
16.
17.
18.
in Gastrin
cyclase
Release
system
and G;!;trlc
In calcitorl
Secretlor
‘: rc!lease
J En
1, 1970
Care AD, Bruce JB. Boelkins J, Kenny 4D. Conaway H Anast CS: Role of pancreozymin-cholecystoklnin antr structurally related compounds as calc~~rn secreta gogues. Endocrinology 89: 262, 197: Care AD, Bruce JB: Calcitonin-releaslrg substances structure-activity relationship. J Enriocrfnci 49: 8 1971. Care AD. Bates RFL, Bruce JB, Swaminathan R. Bloom S, Ganguli PC: Stimulation of calcitonin secretion by gastro-intestinal hormones. J Endocrine: 52: 27, 1972. Cooper CW, Schwesinger WH, Mahgoub AM. Outjes DA Thyrocalcitonin: stimulation of secretion by pentagastrin. Science 172: 1238, 1971 Care AD. Bates RFL, Swaminathan R. Ganguli PC: The role of gastrin as a calcitonin secret,agogue J Endocrinol51: 735, 1971 Cooper CW, Schwesinger WH, Outjes 04, Mahgoub AM. Munson PL: StimLllation of secretion of pig thyrocalcitonin by gastrin and related hormonal peptides Endocrinology 91: 1079, 1972. Phillippo M, Lawrence CB, Bruce JB, Donaldson DR: Feeding and calcitonin secretion in sneep. J Endocrino/ 53: 419,
1972.
19. Go VLW. Sizemore GW, Kaplan EL, Sanzenbacher LS. Holtermuller KH. Arnaud CD: Relationships of calcitonin and gastrin in the Zollinger-Ellison syndrome (Z-E) and medullary carcinoma of the thyroid (MCOT). Gastroenterology 62: 755, 19.72. 20. Becker HD, Konturek SJ, Reeder DD, Thompson JC: Effect of calcium and calcitonin on gastrin and gastric secretion in cats. Am J Physiol225: 27 7 1973. 21. Tenenhouse A, Rasmussen t-i, Nagata N: Parathyroid hormone, 3’5’-AMP and Ca+‘, p 418. Calcitonin 1969. Proceedings of the Second International Symposium, London. July 21-24, 1969. Heidelberg, Springer Verlag, I!369
75
Texas
David D. Reeder, MD, Galveston,
Texas
Murphy T. Scurry, MD, Galveston,
Texas
James C. Thompson, MD, Galveston,
Texas
The relationship between calcium metabolism and gastric secretion has become of increasing interest, since it has been shown that induced hypercalcemia causes an increase in gastric secretion by stimulating the release of gastrin [I]. Calcitonin has been shown to be a potent inhibitor of basal or pentagastrin-stimulated gastric secretion in man [2]. The mechanism by which calcitonin exerts this inhibitory action is not known. The present studies were undertaken to determine the effect of intravenous calcitonin on basal levels of serum gastrin, measured by radioimmuhuman noassay, in normal and hypercalcemic subjects. We further studied the effect of calcitonin on the serum gastrin response to food in normal subjects. Material and Methods Studies were performed on the following human volunteers: eight normal subjects, six patients with duodenal ulcer (DU) disease, three patients with primary hyperparathyroidism (HPT), six patients with histologically proved Zollinger-Ellison (Z-E) syndrome, and From the Departments of Surgery and Internal Medicine, The University of Texas Medical Branch, Galveston, Texas. This work was supported by grants from the National Institutes of Health (AM 15241) and General Clinical Research Centers Branch (DHEW Grant RR 00073) and bv a arant from The John A. Hartford Foundation, Inc. Repiint re&e& should be addressed to Dr Thompson, Oepartinent of Surgery, The University of Texas Medical Branch, Galveston, Texas 77550. Presented at the Fourteenth Annual Meeting of the Society for Surgery of the Alimentary Tract, New York, New York, May 22 and 23, 1973.
Volume 127, January 1974
three patients who had both the Z-E syndrome and HPT (ZE + HPT). The six patients with the Z-E syndrome had had either subtotal or total gastrectomy and had residual tumor as indicated by persistently high levels of serum gastrin. After an overnight fast, patients were given an intravenous infusion of synthetic salmon calcitonin (Ar-2077 calcitonin; Armour Pharmaceutical Co) at a rate of 2 MRCU/kg/hour. Additionally, each patient received 2 MRCIJ/kg as an intravenouszloading dose over the first fifteen minutes of t’he experiment. Effect of Calcitonin on Basal Levels of Serum Gastrin, Serum
Calcium,
and Gastric
Secretion.
Initial
studies were performed in eight normal adult subjects without evidence of gastrointestinal disease. Two blood samples for serum gastrin and calcium determinations were obtained after which the subjects received a ninety minute infusion of calcitonin. Further blood samples were obtained at intervals for 150 minutes after the initiation of the calcitonin infusion. In three of the normal subjects, gastric secretions were aspirated continuously via a sump type nasogastric tube throughout the study, and thirty minute acid outputs were determined. Similar studies were performed in six DU patients, three patients with HPT, six Z-E patients, and three patients with ZE + HPT. The protocol differed slightly in that the calcitonin infusion lasted two hours and the sampling period was for three and a half hours after initiation of the calcitonin infusion. Gastric acid output was measured throughout the studies in all patients except the Z-E patients who had undergone gastrectomy. Effect of Calcitonin on Food-Stimulated Levels of Serum Gastrin in Normal Subjects. In six normal
subjects
paired test-control
studies
were performed
on
71
Becker et al
two different days; the sequence was alternated randomly. In the control study, two basal samples for serum gastrin measurement were obtained after which the patient drank a 500 ml liquid meal containing 52 gm of protein, 7 gm of fat, and 150 gm of carbohydrate. Blood samples were obtained at intervals for 150 minutes. In the test study, this protocol was repeated and, in addition, an intravenous infusion of calcitonin was given over the first sixty minutes after eating. Serum gastrin concentrations in these studies were measured by radioimmunoassay [3]. The antigastrin antibodies currently in use in our laboratory were raised in rabbits using a method described by Vaitukaitis et al [4]; 50 pg of synthetic human gastrin I (amino acid residues 2-17), conjugated to bovine serum albumin, was injected intracutaneously at thirty to fifty sites on the back. In addition, each rabbit was given 0.5 ml of crude pertussis vaccine (Eli Lilly and Co) subcutaneously. Forty days after the initial immunization, the rabbits received a booster injection containing 20 Hg of antigen. Antigastrin antibodies of sufficient system titer for use in the radioimmunoassay (l:lOO,OOO final dilution) were present three months after the initial immunization. Serum gastrin concentrations are expressed as picograms per milliliter (pg/ ml) or as the integrated gastrin response [5] over a given period of time, expressed as nanogram minutes per milliliter (ng-min/ml). Serum calcium concentrations were determined by atomic absorption using the model 303 Perkin-Elmer spectrophotometer. Gastric acid output was determined by titration of a 1 ml sample with 0.1 N NaOH (phenol red used as indicator). Results are expressed as mean values with corresponding standard errors (&SE). The Student t test was used to analyze the significance of differences between means. Statistically significant differences were considered to be those with p values less than 0.05. Results Effect of Calcitonin on Basal Levels of Serum Gastrin, Serum Calcium, and Gastric Secretion. 1. In normal man: In the five normal subjects who were studied without nasogastric intubation, basal serum gastrin concentration was 65 f 2 pg/ml and did not change significantly during the ninety minute calcitonin infusion. (Figure 1.) Basal serum calcium levels of 9.4 f 0.5 mg/lOO ml decreased slightly to 8.9 f 0.2 mg/lOO ml sixty minutes after initiation of the calcitonin infusion. In the three normal subjects in whom gastric acid output was measured, basal serum gastrin levels of 103 f 4 pg/ml and basal serum calcium levels of 8.8 f 0.4 mg/lOO ml were not significantly changed by the calcitonin infusion. Basal gastric acid output was 1.08 f 0.42 mEq per thirty minutes; secretion was completely suppressed in each
72
subject within thirty minutes after initiation of the infusion. 2. In patients with duodenal ulcer (Figure 2): The mean basal serum gastrin concentration in six DU patients was 113 f 9 pg/ml. The mean basal concentration of serum gastrin in the control group of eight normal subjects was 79 f 5 pg/ml; this difference in gastrin values was signficant (p cO.05). After ninety minutes of calcitonin infusion, serum gastrin in the DU patients had fallen to 92 f 6 pg/ml (p X0.05). Serum calcium decreased significantly from a basal value of 8.8 f 0.3 mg/lOO ml to 8.0 f 0.2 mg/lOO ml by sixty minutes after the calcitonin infusion was stopped. The mean basal gastric acid output was 1.27 f 0.29 mEq per thirty minutes, which was inhibited strongly during calcitonin infusion to a low value of 0.05 f 0.04 mEq per thirty minutes (p cO.01). By ninety minutes afier the infusion was stopped, gastric secretion had risen to 0.86 f 0.56 mEq per thirty minutes. 3. In patients with hyperparathyroidism (Figure 3): Mean basal serum gastrin concentration of 157 f 20 pg/ml decreased during calcitonin infusion to 107 f 15 pg/ml at 120 minutes. This decrease in gastrin paralleled a decrease in serum calcium (from 10.9 f 0.7 mg/lOO ml to 9.1 f 0.4 mg/lOO ml). The basal gastric acid output was 1.89 f 0.75 mEq per thirty minutes, which was strongly depressed by calcitonin. (Figure 3.) 4. In patients with Zollinger-Ellison tumors (Figure 4): The mean basal gastrin concentration was 1,498 f 697 pg/ml. During calcitonin infusion serum gastrin decreased to 833 f 506 pg/ml (p cO.05). Serum calcium did not change significantly throughout the experiment. 5. In patients with Zollinger-Ellison tumors and hyperparathyroidism (Figure 5): The mean basal gastrin concentration was 703 f 129 pg/ml, which decreased during calcitonin infusion to 524 f 188 pg/ml at sixty minutes. Serum calcium fell from 10.7 f 0.3 to 9.4 f 0.3 mg/lOO ml. The basal gastric acid output in these three patients was 9.82 f 4.82 mEq per thirty minutes and was abolished by the calcitonin infusion. Effect of Calcitonin on Food-Stimulated Levels of Serum Gastrin in Normal Man (Figure 6). The mean basal serum gastrin concentration in the six normal subjects was 85 f 8 pg/ml on the control day and 76 f 8 pg/ml on the test day. Calcitonin infusion almost totally abolished the serum gastrin response to food. The integrated gastrin output for the 150 minute test period was 2.97 f 1.34 ng-min/ml on the control day and -0.19 f 0.18 ng-min/ml on the test day.
The American Journal of Surgery
Calcitonln
in Gastrin
Release
and bstric
Secretion
5 NORMAL SUBJECTS
!
7:
GASTRIN pg/mi
5” ‘/
,oo,i”\t\. GASTRIN
r-i--_
--_;+--.~”
,ic
pg/mf 75.
__.... --___._ ______. *--- .---.__ _____*____\ Serum C0iCl”rn
0’ CALCIUM ‘90 mq/Kxh
,oo CALCIUM
mg/100mi .80 -60
*---- -_.. ___ . . . ..__ -.----.----.____
50
:
.. serum COlC,“rn
..I:.
<
20 .li
‘10
I/(
1
.__
30
‘80 H’
mEq/30mln
60 MINUTES
Figure 1. Effect of calcitonin on basal levels of serum gastrin and calcium in normal man.
Figure 2. Effect of calcitonin on basal levels of serum gastrin and calcium and on gastric acid output in patients with duodenal ulcer. The asterisk indicates the serum gastrin value to be significantly lower than basal values (p CO. 05).
GASTRIN pghi
LB0
H+ mEq/ 3Omtn
MINUTES
Figure 3. Effect of calcitonin on basal levels of serum gastrin and calcium and on gastric acid output in three patients with primary hyperparathyroidism.
Figure 4. Effect of calcitonin on basal levels of serum gastrin and calcium in patients with the Zollinger-Ellison syndrome who had had gastrectomy. Asterisks identify values significantly lower than basal (p X0.05).
3 PATIENTS
I HYPERPARATHYROIDISM
6 NORMAL
t Z - E SYNDROME
SUBJECTS
1
GASTRIN Pg/ml
Figure 5. Effect of calcitonin on basal levels of serum gastrin and calcium and on gastric acid output in patients who had both hyperparathyroidism and the Zollinger-Ellison syndrome.
Volume
127,
January
1974
Figure 6. Effect of calcitonin on food-stimulated gastrin levels in normal man.
serum
73
Becker et al
Comments
It has been demonstrated that calcitonin has an inhibitory effect on basal or stimulated gastric secretion and on pancreatic secretion in man [Z]. Our results show that calcitonin is a strong inhibitor of basal gastric secretion in normal man and in patients with duodenal ulcer disease, hyperparathyroidism, or Zollinger-Ellison syndrome. The mechanisms of inhibition are still not well understood. The results of the present study show that calcitonin depresses basal levels of serum gastrin in patients who have elevated concentrations of serum gastrin (patients with duodenal ulcer, hyperparathyroidism, and the Zollinger-Ellison syndrome). In normal subjects, however, calcitonin decreases basal gastric secretion strongly without changing basal serum gastrin levels. The results thus provide evidence that calcitonin inhibits gastric secretion by two separate mechanisms. First, calcitonin apparently acts directly at the parietal cell, and second, it decreases elevated levels of serum gastrin. This decrease in serum gastrin concentration could be explained either by depression of the release of gastrin or by activation of catabolic mechanisms; our studies do not allow a choice between these two possibilities. Gastrin is known to exist in at least three molecular sizes. The originally described form had 17-amino acids with a molecular weight of about 2100 [6]. Yalow and Berson [7,8] have shown that there is a larger form of gastrin with a molecular weight of around 7000 which predominates in the circulation. This larger form has 34-amino acids [9] and appears to be increased in circulating plasma after a meal [S]. A possible explanation for the action of calcitonin is that it has differential effects on the release (or catabolic) mechanisms affecting the different forms of gastrin. Previous studies from our laboratory have shown that in patients with duodenal ulcer, secretin [5] and glucagon [IO] have effects on gastric secretion and gastrin that are similar to those of calcitonin. There is a difference, however, in that both secretin and glucagon may suppress basal levels of gastrin in normal subjects and elevate levels of gastrin in patients with the Zollinger-Ellison syndrome. Glucagon caused a decrease in levels of serum calcium; secretin did not [9]. There have been many recent studies on the relation between gastrointestinal hormones and the secretion of calcitonin. It has been shown that glucagon [11], cholecystokinin (CCK) [12-141, the
74
C-terminal octapeptide of CCK [12], caerulein [12], pentagastrin [12,15-181, pure porcine gastrin II [14], and synthetic human gastrin I [14] are stimulants for the release of calcitonin from the thyroid of pigs. Care and co-workers [11-14,161 showed that endogenous gastrin caused a significant release of calcitonin in pigs. Furthermore, Phillippo and associates [18] found an immediate increase of calcitonin in sheep after food intake. Go and co-workers [19] reported high serum calcitonin levels in patients with Zollinger-Ellison tumors and low serum gastrin levels in patients with medullary carcinoma of the thyroid. In recent studies we have found that calcitonin depresses calcium-induced hypergastrinemia in cats (201. These results lead to the speculation that calcitonin may have a regulatory function in the release and catabolism of the gastrointestinal hormones. The present studies show that dalcitonin depresses serum calcium levels significantly in patients with hypercalcemia and only slightly depresses serum calcium in persons with normal values. These findings provide evidence that the depression of serum gastrin and of gastric secretion by calcitonin is independent of the serum calcium levels. Tenenhouse, Rasmussen, and Nagata [21] postulated that calcitonin acts by altering cellular calcium exchange by a direct activation of the calcium pump. That could explain our findings in cats [20], in which calcitonin strongly inhibited pentagastrinand histamine-stimulated gastric secretion. Summary We studied the effect of an intravenous infusion of calcitonin (2 MRCU/kg) on gastric secretion and serum gastrin and serum calcium levels in eight normal subjects, six patients with duodenal ulcer disease, three patients with primary hyperparathyroidism, six patients with histologically proved Zollinger-Ellison syndrome, and three patients with the Zollinger-Ellison syndrome and hyperparathyroidism. Gastric secretion was greatly inhibited in all groups of patients. Serum calcium was significantly diminished only in patients with hypercalcemia. Serum gastrin levels were depressed in all patients with elevated basal gastrin levels (DU, HPT, Z-E, and ZE + HPT). In normal subjects calcitonin inhibited strongly the serum gastrin response to food. These findings suggest that calcitonin may have a regulatory function in the release or catabolism of the hormone gastrin.
The American Journal of Surgery
Calcitonin
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