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Effect of bombesin on serum immunoreactive trypsin in healthy subjects and in patients with chronic pancreatitis
GASTROENTEROLOGY 1983;85:323-7
Effect of Bombesin on Serum Immunoreactive Trypsin in Healthy Subjects and in Patients With Chronic Pancreatitis G. LAB& P. VEZZADINI, and G. BONORA
L. GULLO,
C. STERNINI,
First Medical Clinic, University of Bologna, Bologna, Italy
We studied the effect of bombesin [9 &kg * min for 30 min by intravenous infusion) on serum immunoreactive trypsin in healthy subjects and in chronic pancreatitis patients. Bombesin administration caused a marked and significant increase of serum immunoreactive trypsin concentration in healthy subjects. The increase occurred in the first 15 min after the beginning of bombesin infusion and persisted for the duration of the study [Z h). In patients with chronic pancreatitis, the increase was much less pronounced. In these patients, the integrated immunoreactive trypsin response to bombesin was significantly correlated with bicarbonate, Jipase, and chymotrypsin outputs into the duodenum. The response of serum immunoreactive trypsin to bombesin stimulation seems to vary according to the degree of pancreatic exocrine dysfunction and to reflect the functional capacity of acinar cell mass. Bombesin, a tetradecapeptide isolated from amphibian skin that displays a wide spectrum of biologic actions on the mammalian gastrointestinal tract, is a powerful stimulant of pancreatic exocrine secretion in several species, including humans (1-6).The mechanism of action is unknown. It has been suggested that bombesin may exert its effect on the pancreas indirectly, through the release of cholecystokinin (I$), or directly, interacting with specific receptors on the pancreatic acinar cells (7-11). Received April 5, 1982. Accepted February 11, 1983. Address requests for reprints to: Giuseppe Labb, M.D., Clinica Medica I, Universita di Bologna, Policlinico S. Orsola, via Massarenti 9, 40138 Bologna, Italia. This study was supported by a grant from the National Research Council of Rome (Italy) (CT 80.00479.04). The authors thank Angela Favaro, B.Sc., for technical assistance, and Daniele Agostini, M.D., for statistical analysis. 0 1983 by the American Gastroenterological Association 0016~5085/83/$3.00
The development of radioimmunoassay techniques led to the measurement of serum immunoreactive trypsin (IRT), an organospecific pancreatic protein (12), which has been recently proposed as a reliable marker of the functional capacity of the In previous studies, it has been acinar cells (13,14). shown that serum IRT was not affected by cholecystokinin (l&15) or cerulein infusion (la), whereas it was slightly increased by secretin intravenous infusion (14) or injection (16).The present study was carried out to assess the effect of bombesin administration on serum IRT concentration in healthy subjects and in patients with chronic pancreatitis. Moreover, we correlated the serum IRT levels after bombesin administration with pancreatic bicarbonate and enzyme outputs into the duodenum to ascertain whether a relation existed between serum IRT response to bombesin and pancreatic exocrine function.
Materials and Methods The study was carried out on two groups of subjects. The first group included 11 healthy volunteers (8 men and 3 women; average age 42 yr; range 19-80 yr). None of them had clinical or biochemical evidence of upper gastrointestinal, pancreatic, or hepatobiliary disease. None were alcoholic [alcohol ingestion ~50 g/day) or had renal or metabolic disorders. Seven were cigarette smokers (10-40 cigarettes daily for 5-30 yr). The second group included 15 patients (13 men and 2 women; mean age 43 yr; range 32-60 yr) with chronic pancreatitis. Chronic pancreatitis was of alcoholic origin in 11 patients (alcohol intake ~50 g/day for >6 yr) and idiopathic in the remaining 4 patients. Serum transaminases, serum albumin and protein electrophoresis, total bilirubin and fractions, alkaline phosphatase, blood urea, and serum creatinine were within the normal range in all patients, whereas yGT was elevated in 4 patients. None of these patients had endoscopic evidence of esophageal varices or
324
LAB0
GASTROENTEROLOGY Vol. 85, No. 2
ET AL.
BOMBESIN
5200. c z c & I- 150 " 2 L lz 5 5 loo: : g
50-
O-
6 5
15
30
i5
60
90
120
MINUTES
Figure
1
Serum
immunoreactive trypsin response (mean + SEM) to bombesin infusion in control subjects and in
chronic pancreatitis patients. Bars indicate mean + 1 SEM; *, p < 0.01 when compared with basal value; A, p < 0.05; AA, p < 0.001 when compared with control subjects. evidence of portal hypertension on ultrasonography. Ten were cigarette smokers (15-40 cigarettes daily for 15-40 yr). The diagnosis of chronic pancreatitis was based on clinical, biochemical, and radiologic data. It was confirmed by radiologic evidence of pancreatic calcification in 10 patients, and by the presence of impaired secretory response to the secretin-cerulein test or by typical abnormalities of the pancreatic ductal system at endoscopic retrograde cholangiopancreatography, or by both, in the remaining 5 patients. None of the patients was suffering from exacerbation of pain at the time of the study. All subjects gave informed consent. Pancreatic exocrine function was studied in 12 of the 15 patients with chronic pancreatitis, using a method previously described (17). After an overnight fast, each of these patients underwent duodenal intubation and duodenal juice was collected at 15-min intervals for 90 min during intravenous infusion of secretin (GIH, 1 CUikg . h) and synthetic cerulein (100 ngikg . h). Bicarbonate, lipase, and chymotrypsin outputs during the last 30 min of stimulation were taken as a measure of the functional capacity of the pancreas (17). The bombesin test was performed in each subject after an overnight fast. Three to 7 days elapsed between duodenal intubation and bombesin test in patients with chronic pancreatitis. Bombesin (Farmitalia, Milan, Italy), in a dose of 9 rig/kg. min, was diluted with saline (0.9% NaCl) and was administered at a constant rate in 30 min. Blood samples were taken immediately before and at 5, 15, 30, 45, 60, 90, and 120 min after the beginning of bombesin infusion. Serum samples were frozen until assay. Serum
IRT was measured by radioimmunoassay, according to the method described by Malvano et al. (18). This assay is commercially available as “Trypsik-kit,” Sorin-Biomedica (Saluggia, Vercelli, Italy). The reproducibility of the method was tested by evaluating the within-assay and betweenassay variability for duplicate determinations of three different samples measured 10 times in the same assay or in a series of 10 consecutive assays. At concentrations of IRT of 9, 33, and 80 ng/ml, the within-assay coefficients of variations were 6.10,, 7.3%, and 9.8%, and the betweenassay coefficients were 8.0%, 9.1%, and 11.7%, respectively. No interference by bombesin was shown in serum trypsin radioimmunoassay at the concentrations used in the present study. The results were expressed as the serum concentration of IRT (ngiml) at the different times of the test and as the integrated IRT response above basal values over the 120-min period (pg * miniml). The integrated response was calculated according to Ippoliti et al. (19). The Wilcoxon test for paired and unpaired data and Spearman’s correlation test were used for statistical analysis. Differences with a p-value of co.05 were considered significant. Side effects, blood pressure, and heart rate were evaluated in each subject during the bombesin infusion. Only a few subjects complained of nausea, which was always transitory, spontaneously disappeared at the end of the bombesin infusion, and never hindered the continuation of the test. Blood pressure and heart rate were not modified by administration of bombesin.
Results Figure 1 shows serum IRT levels (mean * SEM) before and after bombesin stimulation in healthy subjects and in chronic pancreatitis patients. The mean basal concentration of serum IRT in patients with chronic pancreatitis was lower than in control subjects. The difference, however, was not statistically significant. Bombesin administration caused a marked and significant increase of serum IRT in healthy subjects. The increase was rapid, reached a peak at 60 min after the beginning of bombesin infusion, and persisted for the duration of the test. In patients with chronic pancreatitis, the increase of serum IRT after bombesin stimulation was much less marked. In 4 patients with severe pancreatic exocrine insufficiency at duodenal intubation (enzyme outputs
August
BOMBESIN AND SERUM IMMUNOREACTIVE
1983
TRYPSIN
325
(none of these had steatorrhea). In these patients, the integrated IRT response to bombesin was significantly correlated (Figure 3) with the bicarbonate (r, = 0.674,p < 0.05),lipase (r, = 0.815, p < O.Ol), and chymotrypsin (r, = 0.768,p < 0.05)outputs into the duodenum. The latter enzyme is not shown in the figure for brevity.
Discussion . :
. .
.
:* t ?? ?? ? ?? ???? ?? ???? CONTROL SUBJECTS n = 11
Figure
CHHONIC PANCREATITIS n= 15
2. Integrated immunoreactive trypsin response to bombesin stimulation in control subjects and in chronic pancreatitis
patients.
The lines
indicate
mean
value.
the controls. The difference between the two groups was significant (p < 0.01). Of the 12 chronic pancreatitis patients who underwent the secretin-cerulein test, 4 had severe pancreatic insufficiency, i.e., enzyme outputs
.
n ;L 12 r, = 0.815 p < 0.01
??
The results of this study show that bombesin, at a dose of 9 ng/kg * min, strongly increases serum IRT concentration in healthy subjects, whereas it has little effect in chronic pancreatitis patients. The causes of the increase of serum IRT levels after bombesin infusion are unknown. The appearance of peak serum IRT levels 30 min after the end of bombesin infusion suggests the possibility of an intestinal absorption of trypsin (20,21) or, alternatively, of an indirect effect of the peptide involving the release of some unknown mediator. The failure to detect significant rises in serum IRT concentration after a meal (15,22),however, or after cholecystokinin (14,15)and secretin plus cerulein (23) administration, does not seem to support the first hypothesis. Whether bombesin acts on the release of IRT indirectly by hormonal as well as neural mediators remains to be elucidated. Moreover, since we used an unphysiologic dose of bombesin, the possibility that the increase of serum IRT was due to a reversible acinar cell damage produced by this particular dose of peptide cannot be ruled out. This could also account for the prolonged effect of bombesin. In patients with chronic pancreatitis, the mean
.
.
n = 12 r, L 0.674 p e 0.05
.
.
. .
a .
. . .
LIPASE Correlation between into the duodenum
OUTPUT
.
Ux103/30
integrated immunoreactive during secretin-cerulein
min
6
7
w-0
55
BICARBONATE
14
OUTPUT mmol/30min
trypsin response to bombesin stimulation and lipase infusion in 12 patients with chronic pancreatitis.
and bicarbonate
outputs
326
LAB0
ET AL.
basal serum IRT concentration, although lower, was not significantly different from that of control subjects. The discrepancy with other investigators, who found a significant difference in the mean basal serum IRT levels between chronic pancreatitis patients and controls (15,23,24), may be due to a different degree of pancreatic exocrine insufficiency in the various patients studied. In fact, we (25) and other investigators (13,14) have shown that the basal levels of serum IRT are very low in chronic pancreatitis patients with severe pancreatic insufficiency, but they are generally normal in patients with mildto-moderate insufficiency. In chronic pancreatitis patients, the rise in serum IRT after bombesin stimulation was much less pronounced, as compared with healthy subjects, or even absent in patients with more severe pancreatic insufficiency. This different behavior cannot be explained by differences in sex, age, or smoking habits, since the two groups of subjects were comparable with regard to these factors. The only difference between controls and chronic pancreatitis patients was that most of the patients (11 of 15) were heavy drinkers. It is unlikely, however, that alcoholism was responsible for the different results obtained in the two groups, since abnormally low values of serum IRT response to bombesin were also found in 3 of the 4 chronic pancreatitis patients who were not drinkers. The significant correlation between serum IRT response to bombesin administration and pancreatic bicarbonate, lipase, and chymotrypsin outputs into the duodenum suggests that the release of IRT into the circulation after bombesin stimulation varies according to the degree of exocrine pancreatic dysfunction, and that it may reflect the functional capacity of acinar cell mass. In this study, an abnormal response of serum IRT to bombesin was detected in 80% of patients. If we take into account that the majority of patients studied had mild-to-moderate pancreatic exocrine insufficiency, it seems that the diagnostic value of this simple, noninvasive test is satisfactory. On the basis of our preliminary results, however, it is difficult to say whether measurement of serum IRT after bombesin administration can replace other tests of pancreatic function in the evaluation of the individual patient. A comprehensive study of the sensitivity of serum IRT response to bombesin in the diagnosis of pancreatic diseases in comparison with other tests is currently in progress.
References 1. Erspamer V, Improta G, Melchiorri P, Sopranzi N. Evidence of cholecystokinin release by bombesin in the dog. Br J Pharmaco1 1974;52:227-32.
GASTROENTEROLOGY
Vol.
85, No.
2
2. Basso N, Giri S, Improta G, et al. External pancreatic secretion after bombesin infusion in man. Gut 1975;16:994-8. 3. Linari G, Baldieri Linari M. Effect of bombesin on pancreatic secretion and gallbladder motility of the chicken. Em J Pharmacol 1975;34:305-10. 4. Konturek SJ, Krol R, Tasler J. Effect of bombesin and related peptides on the release and action of intestinal hormones on pancreatic secretion. J Physiol 1976;257:663-72. 5. Miyata M, Rayford PL, Thompson JC. Hormonal (gastrin, secretin, cholecystokinin) and secretory effects of bombesin and duodenal acidification in dogs. Surgery 1980:87:209-15. 6. Singer MV, Niebel W, Lamers C, et al. Effects of truncal vagotomy and antrectomy on bombesin-stimulated pancreatic secretion, release of gastrin and pancreatic polypeptide in the anesthetized dog. Dig Dis Sci 1981;26:871-7. 7. Deschodt-Lanckman M, Robberecht P, De Neef P, Lammens M, Christophe J. In vitro action of bombesin and bombesinlike peptides on amylase secretion, calcium efflux and adenylate cyclase activity in the rat pancreas. J Clin Invest 1976;58:891-8. 8. Iwatsuki N, Petersen OH. In vitro action of bombesin on amylase secretion, membrane potential and membrane resistance in rat and mouse pancreatic acinar cells. A comparison with other secretagogues. J Clin Invest 1978;61:41-46. 9. May RJ, Conlon TP, Erspamer V, Gardner JD. Actions of peptides isolated from amphibian skin on pancreatic acinar cells. Am J Physiol 1978;235:E112-8. 10. Jensen RT, Moody T, Pert C, Rivier JE, Gardner JD. Interaction of bombesin and litorin with specific membrane receptors on pancreatic acinar cells. Proc Nat1 Acad Sci USA 1978; 75:6139-43. 11. Gardner JD. Regulation of pancreatic exocrine function in vitro: initial steps in the actions of secretagogues. Annu Rev Physiol 1979;41:55-66. 12. Temler RS, Felber JP. Radioimmunoassay of human plasma trypsin. Biochim Biophys Acta 1976;445:720-8. 13. Adrian TE, Besterman HS, Mallinson CN, et al. Plasma trypsin in chronic pancreatitis and pancreatic adenocarcinoma. Clin Chim Acta 1979;97:205-12. 14. Adrian TE. Plasma trypsin-like immunoreactivity in normal subjects and in patients with pancreatic diseases. Stand J Gastroenterol 1980;15(Suppl 62):15-20. 15. Koop H, Lankisch PG, Stockmann F. Arnold R. Trypsin radioimmunoassay in the diagnosis of chronic pancreatitis. Digestion 1980;20:151-6. 16. Vezzadini P, Ferri GL, Bonora G, et al. Secretin-stimulated trypsin-like immunoreactivity in alcoholics. Clin Chim Acta 1981;111:163-7. 17. Gullo L, Costa PL, Fontana G, Labb G. Investigation of exocrine pancreatic function by continuous infusion of caerulein and secretin in normal subjects and in chronic pancreatitis. Digestion 1976;14:97-107. 18. Malvano R, Marchisio M, Massaglia A, et al. Radioimmunoassay of trypsin-like substance in human serum. Stand J Gastroenterol 1980;15(Suppl 62):3-10. 19. Ippoliti AF, Isenberg JI, Hagie L. Effect of oral and intravenous 16, 16-dimethyl prostaglandin E, in duodenal ulcer and Zollinger-Ellison syndrome patients. Gastroenterology 1981;80:55-9. 20. Lake-Bakaar G, Rubio CE, Kavanagh S, Potter BJ, Summerfield JA. Metabolism of 1251-labelled trypsin in man: evidence for recirculation. Gut 1980;21:580-6.. 21. Lake-Bakaar G. Smith-Laina G, Summerfield IA. Oriain of circulating serum immunoreactive trypsin in man. Dig Dis Sci 1982;27:143-8. 22. Bonora G, Tomassetti P, Sternini C, Bagnoli L, Agostini D,
August
1983
Vezzadini P. Basal and stimulated serum immunoreactive trypsin in normal subjects. Stand J Gastroenterol 1980;15 (Suppl 62):11-4. 23. Andriulli A, Recchia S, Masoero G, et al. Clinical evaluation of serum cationic trypsin-like immunoreactivity in patients with different pancreatic diseases. Ital J Gastroenterol 1980;12:260-4.
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TRYPSIN
327
24. Andriulli A, Masoero G, Felder M, et al. Circulating trypsinlike immunoreactivity in chronic pancreatitis. Dig Dis Sci 1981;26:532-7. 25. Gullo L, Ventrucci M, Bonora G, Gori G, Vezzadini P. Comparative study of serum trypsin levels and pancreatic exocrine function in chronic pancreatitis. Stand J Gastroenterol 1980;15(Suppl 62):27-8.
Effect of Bombesin on Serum Immunoreactive Trypsin in Healthy Subjects and in Patients With Chronic Pancreatitis G. LAB& P. VEZZADINI, and G. BONORA
L. GULLO,
C. STERNINI,
First Medical Clinic, University of Bologna, Bologna, Italy
We studied the effect of bombesin [9 &kg * min for 30 min by intravenous infusion) on serum immunoreactive trypsin in healthy subjects and in chronic pancreatitis patients. Bombesin administration caused a marked and significant increase of serum immunoreactive trypsin concentration in healthy subjects. The increase occurred in the first 15 min after the beginning of bombesin infusion and persisted for the duration of the study [Z h). In patients with chronic pancreatitis, the increase was much less pronounced. In these patients, the integrated immunoreactive trypsin response to bombesin was significantly correlated with bicarbonate, Jipase, and chymotrypsin outputs into the duodenum. The response of serum immunoreactive trypsin to bombesin stimulation seems to vary according to the degree of pancreatic exocrine dysfunction and to reflect the functional capacity of acinar cell mass. Bombesin, a tetradecapeptide isolated from amphibian skin that displays a wide spectrum of biologic actions on the mammalian gastrointestinal tract, is a powerful stimulant of pancreatic exocrine secretion in several species, including humans (1-6).The mechanism of action is unknown. It has been suggested that bombesin may exert its effect on the pancreas indirectly, through the release of cholecystokinin (I$), or directly, interacting with specific receptors on the pancreatic acinar cells (7-11). Received April 5, 1982. Accepted February 11, 1983. Address requests for reprints to: Giuseppe Labb, M.D., Clinica Medica I, Universita di Bologna, Policlinico S. Orsola, via Massarenti 9, 40138 Bologna, Italia. This study was supported by a grant from the National Research Council of Rome (Italy) (CT 80.00479.04). The authors thank Angela Favaro, B.Sc., for technical assistance, and Daniele Agostini, M.D., for statistical analysis. 0 1983 by the American Gastroenterological Association 0016~5085/83/$3.00
The development of radioimmunoassay techniques led to the measurement of serum immunoreactive trypsin (IRT), an organospecific pancreatic protein (12), which has been recently proposed as a reliable marker of the functional capacity of the In previous studies, it has been acinar cells (13,14). shown that serum IRT was not affected by cholecystokinin (l&15) or cerulein infusion (la), whereas it was slightly increased by secretin intravenous infusion (14) or injection (16).The present study was carried out to assess the effect of bombesin administration on serum IRT concentration in healthy subjects and in patients with chronic pancreatitis. Moreover, we correlated the serum IRT levels after bombesin administration with pancreatic bicarbonate and enzyme outputs into the duodenum to ascertain whether a relation existed between serum IRT response to bombesin and pancreatic exocrine function.
Materials and Methods The study was carried out on two groups of subjects. The first group included 11 healthy volunteers (8 men and 3 women; average age 42 yr; range 19-80 yr). None of them had clinical or biochemical evidence of upper gastrointestinal, pancreatic, or hepatobiliary disease. None were alcoholic [alcohol ingestion ~50 g/day) or had renal or metabolic disorders. Seven were cigarette smokers (10-40 cigarettes daily for 5-30 yr). The second group included 15 patients (13 men and 2 women; mean age 43 yr; range 32-60 yr) with chronic pancreatitis. Chronic pancreatitis was of alcoholic origin in 11 patients (alcohol intake ~50 g/day for >6 yr) and idiopathic in the remaining 4 patients. Serum transaminases, serum albumin and protein electrophoresis, total bilirubin and fractions, alkaline phosphatase, blood urea, and serum creatinine were within the normal range in all patients, whereas yGT was elevated in 4 patients. None of these patients had endoscopic evidence of esophageal varices or
324
LAB0
GASTROENTEROLOGY Vol. 85, No. 2
ET AL.
BOMBESIN
5200. c z c & I- 150 " 2 L lz 5 5 loo: : g
50-
O-
6 5
15
30
i5
60
90
120
MINUTES
Figure
1
Serum
immunoreactive trypsin response (mean + SEM) to bombesin infusion in control subjects and in
chronic pancreatitis patients. Bars indicate mean + 1 SEM; *, p < 0.01 when compared with basal value; A, p < 0.05; AA, p < 0.001 when compared with control subjects. evidence of portal hypertension on ultrasonography. Ten were cigarette smokers (15-40 cigarettes daily for 15-40 yr). The diagnosis of chronic pancreatitis was based on clinical, biochemical, and radiologic data. It was confirmed by radiologic evidence of pancreatic calcification in 10 patients, and by the presence of impaired secretory response to the secretin-cerulein test or by typical abnormalities of the pancreatic ductal system at endoscopic retrograde cholangiopancreatography, or by both, in the remaining 5 patients. None of the patients was suffering from exacerbation of pain at the time of the study. All subjects gave informed consent. Pancreatic exocrine function was studied in 12 of the 15 patients with chronic pancreatitis, using a method previously described (17). After an overnight fast, each of these patients underwent duodenal intubation and duodenal juice was collected at 15-min intervals for 90 min during intravenous infusion of secretin (GIH, 1 CUikg . h) and synthetic cerulein (100 ngikg . h). Bicarbonate, lipase, and chymotrypsin outputs during the last 30 min of stimulation were taken as a measure of the functional capacity of the pancreas (17). The bombesin test was performed in each subject after an overnight fast. Three to 7 days elapsed between duodenal intubation and bombesin test in patients with chronic pancreatitis. Bombesin (Farmitalia, Milan, Italy), in a dose of 9 rig/kg. min, was diluted with saline (0.9% NaCl) and was administered at a constant rate in 30 min. Blood samples were taken immediately before and at 5, 15, 30, 45, 60, 90, and 120 min after the beginning of bombesin infusion. Serum samples were frozen until assay. Serum
IRT was measured by radioimmunoassay, according to the method described by Malvano et al. (18). This assay is commercially available as “Trypsik-kit,” Sorin-Biomedica (Saluggia, Vercelli, Italy). The reproducibility of the method was tested by evaluating the within-assay and betweenassay variability for duplicate determinations of three different samples measured 10 times in the same assay or in a series of 10 consecutive assays. At concentrations of IRT of 9, 33, and 80 ng/ml, the within-assay coefficients of variations were 6.10,, 7.3%, and 9.8%, and the betweenassay coefficients were 8.0%, 9.1%, and 11.7%, respectively. No interference by bombesin was shown in serum trypsin radioimmunoassay at the concentrations used in the present study. The results were expressed as the serum concentration of IRT (ngiml) at the different times of the test and as the integrated IRT response above basal values over the 120-min period (pg * miniml). The integrated response was calculated according to Ippoliti et al. (19). The Wilcoxon test for paired and unpaired data and Spearman’s correlation test were used for statistical analysis. Differences with a p-value of co.05 were considered significant. Side effects, blood pressure, and heart rate were evaluated in each subject during the bombesin infusion. Only a few subjects complained of nausea, which was always transitory, spontaneously disappeared at the end of the bombesin infusion, and never hindered the continuation of the test. Blood pressure and heart rate were not modified by administration of bombesin.
Results Figure 1 shows serum IRT levels (mean * SEM) before and after bombesin stimulation in healthy subjects and in chronic pancreatitis patients. The mean basal concentration of serum IRT in patients with chronic pancreatitis was lower than in control subjects. The difference, however, was not statistically significant. Bombesin administration caused a marked and significant increase of serum IRT in healthy subjects. The increase was rapid, reached a peak at 60 min after the beginning of bombesin infusion, and persisted for the duration of the test. In patients with chronic pancreatitis, the increase of serum IRT after bombesin stimulation was much less marked. In 4 patients with severe pancreatic exocrine insufficiency at duodenal intubation (enzyme outputs
August
BOMBESIN AND SERUM IMMUNOREACTIVE
1983
TRYPSIN
325
(none of these had steatorrhea). In these patients, the integrated IRT response to bombesin was significantly correlated (Figure 3) with the bicarbonate (r, = 0.674,p < 0.05),lipase (r, = 0.815, p < O.Ol), and chymotrypsin (r, = 0.768,p < 0.05)outputs into the duodenum. The latter enzyme is not shown in the figure for brevity.
Discussion . :
. .
.
:* t ?? ?? ? ?? ???? ?? ???? CONTROL SUBJECTS n = 11
Figure
CHHONIC PANCREATITIS n= 15
2. Integrated immunoreactive trypsin response to bombesin stimulation in control subjects and in chronic pancreatitis
patients.
The lines
indicate
mean
value.
the controls. The difference between the two groups was significant (p < 0.01). Of the 12 chronic pancreatitis patients who underwent the secretin-cerulein test, 4 had severe pancreatic insufficiency, i.e., enzyme outputs
.
n ;L 12 r, = 0.815 p < 0.01
??
The results of this study show that bombesin, at a dose of 9 ng/kg * min, strongly increases serum IRT concentration in healthy subjects, whereas it has little effect in chronic pancreatitis patients. The causes of the increase of serum IRT levels after bombesin infusion are unknown. The appearance of peak serum IRT levels 30 min after the end of bombesin infusion suggests the possibility of an intestinal absorption of trypsin (20,21) or, alternatively, of an indirect effect of the peptide involving the release of some unknown mediator. The failure to detect significant rises in serum IRT concentration after a meal (15,22),however, or after cholecystokinin (14,15)and secretin plus cerulein (23) administration, does not seem to support the first hypothesis. Whether bombesin acts on the release of IRT indirectly by hormonal as well as neural mediators remains to be elucidated. Moreover, since we used an unphysiologic dose of bombesin, the possibility that the increase of serum IRT was due to a reversible acinar cell damage produced by this particular dose of peptide cannot be ruled out. This could also account for the prolonged effect of bombesin. In patients with chronic pancreatitis, the mean
.
.
n = 12 r, L 0.674 p e 0.05
.
.
. .
a .
. . .
LIPASE Correlation between into the duodenum
OUTPUT
.
Ux103/30
integrated immunoreactive during secretin-cerulein
min
6
7
w-0
55
BICARBONATE
14
OUTPUT mmol/30min
trypsin response to bombesin stimulation and lipase infusion in 12 patients with chronic pancreatitis.
and bicarbonate
outputs
326
LAB0
ET AL.
basal serum IRT concentration, although lower, was not significantly different from that of control subjects. The discrepancy with other investigators, who found a significant difference in the mean basal serum IRT levels between chronic pancreatitis patients and controls (15,23,24), may be due to a different degree of pancreatic exocrine insufficiency in the various patients studied. In fact, we (25) and other investigators (13,14) have shown that the basal levels of serum IRT are very low in chronic pancreatitis patients with severe pancreatic insufficiency, but they are generally normal in patients with mildto-moderate insufficiency. In chronic pancreatitis patients, the rise in serum IRT after bombesin stimulation was much less pronounced, as compared with healthy subjects, or even absent in patients with more severe pancreatic insufficiency. This different behavior cannot be explained by differences in sex, age, or smoking habits, since the two groups of subjects were comparable with regard to these factors. The only difference between controls and chronic pancreatitis patients was that most of the patients (11 of 15) were heavy drinkers. It is unlikely, however, that alcoholism was responsible for the different results obtained in the two groups, since abnormally low values of serum IRT response to bombesin were also found in 3 of the 4 chronic pancreatitis patients who were not drinkers. The significant correlation between serum IRT response to bombesin administration and pancreatic bicarbonate, lipase, and chymotrypsin outputs into the duodenum suggests that the release of IRT into the circulation after bombesin stimulation varies according to the degree of exocrine pancreatic dysfunction, and that it may reflect the functional capacity of acinar cell mass. In this study, an abnormal response of serum IRT to bombesin was detected in 80% of patients. If we take into account that the majority of patients studied had mild-to-moderate pancreatic exocrine insufficiency, it seems that the diagnostic value of this simple, noninvasive test is satisfactory. On the basis of our preliminary results, however, it is difficult to say whether measurement of serum IRT after bombesin administration can replace other tests of pancreatic function in the evaluation of the individual patient. A comprehensive study of the sensitivity of serum IRT response to bombesin in the diagnosis of pancreatic diseases in comparison with other tests is currently in progress.
References 1. Erspamer V, Improta G, Melchiorri P, Sopranzi N. Evidence of cholecystokinin release by bombesin in the dog. Br J Pharmaco1 1974;52:227-32.
GASTROENTEROLOGY
Vol.
85, No.
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