Pancreatic Polypeptide Response in Patients with Chronic Pancreatitis J O R G E E. V A L E N Z U E L A ,
MD, I A N L. T A Y L O R , MD, and J O H N H. W A L S H , M D
We studied the plasma pancreatic polypeptide (PP) response to a meal in patients with pancreatitis and attempted to correlate the PP increment with the degree of pancreatic exocrine insufficiency. Control subjects and patients with recurrent pancreatitis showed significant mean increase (P < 0.05) in plasma PP concentration in response to food. By contrast chronic pancreatitis patients had no significant increase in plasma PP. However, some subjects with normal pancreatic secretion had no response and some patients with chronic pancreatitis did show a response. In addition, no correlation was observed between the PP response and pancreatic exocrine secretion. We conclude that the PP response to a meal has only limited value in the detection of pancreatic destruction.
Pancreatic polypeptide (PP) is a peptide o f 36 amino acid residues which was initially discovered as an apparent c o n t a m i n a n t in chicken and bovine insulins (1-3). As the name suggests PP is found alm o s t exclusively in the p a n c r e a s within which its cell of origin has a unique distribution (4). Unlike other pancreatic endocrine cells, the PP cell is not restricted to the islets of L a n g e r h a n s but is found scattered in the p a r e n c h y m a of the exocrine pancreas and in the epithelium of the pancreatic ducts (5). Total p a n c r e a t e c t o m y abolishes the increase in circulating PP seen after a meal (4), suggesting that loss of the PP r e s p o n s e to food might be anticipated in patients with pancreatic destruction s e c o n d a r y to chronic pancreatitis. The p u r p o s e o f the present study was to determine the characteristics of the PP response to a meal in patients with different stages of pancreatitis and to determine w h e t h e r the PP response to food could be correlated with the impairm e n t of exocrine pancreatic secretion.
Manuscript received April 17, 1979; revised manuscript received June 25, 1979; accepted June 29, 1979. From the Gastroenterology Division, University of Southern California and VA Wadsworth Hospital Center, Los Angeles, California. Address for reprint requests: Dr. J.E. Valenzuela, Gastroenterology Division, USC Medical School, 2025 Zonal Avenue, Los Angeles, California 90033.
862
M A T E R I A L S AND M E T H O D S This investigation was approved by the Los Angeles County-University of Southern California Human Research Committee (#01075) and each of the subjects gave informed consent. Twenty-nine patients (22 male and 7 female; mean age 49; range 30-79 years) had chronic alcoholic pancreatitis diagnosed by clinical history of recurrent pancreatitis in all, presence of pancreatic calcification on abdominal radiography (13/29), gross abnormalities of the pancreatic ductal system by endoscopic retrograde pancreatography (16/16), abnormal blood sugar levels (15/29), and steatorrhea (23/29). In addition 16 of the 29 patients had secretin-cholecystokinin test that showed low bicarbonate concentration and decreased pancreatic trypsin (6) secretion suggestive of chronic pancreatitis in all of them. All patients had either pancreatic calcifications and/or abnormal ducts on ERCP and/or exocrine insufficiency on duodenal aspiration. None of the patients had symptoms of acute pancreatitis at the time of the study. Eleven patients (7 male and 4 female; mean age 47; range 19-71 years) were diagnosed as having recurrent pancreatitis by clinical history of at least two well-documented episodes of acute pancreatitis but without presence of radiological abnormalities of the pancreas, normal blood sugar, absence of steatorrhea and normal response to secretin-cholecystokinin stimulation in the four patients in whom this study was performed. Nine of these subjects were chronic alcoholics and two had associated biliary tract disease. Twenty-one subjects (14 males, 7 females; mean age 41 years; range 31-70 years) free of gastrointestinal or other medical disease served as controls. Digestive Diseases and Sciences, Vol. 24, No. 11 (November 1979)
0163-2116/79/1100-0862503.00/1 9 1979DigestiveDisease Systems, Inc.
PANCREATIC POLYPEPTIDE IN PANCREATITIS TABLE 1. EFFECT OF A MEAL ON PLASMA PANCREATIC POLYPEPTIDE (PIcOMOLES PER LITER) IN NORMAL SUBJECTS AND PATIENTS WITH PANCREATITIS*
PP
Controls(21)t Recurrent pancreatitis (11) Chronic pancreatitis(29)
Age
Male~ female
Response to food (A)
47 --- 5
2:1
30 -
5
175 --- 35~
47 --- 4
2:1
39 +- 12
139 --- 48:~
49 - 6
3:1
21 --- 9
36 --- 5w
Basal
*Results are e x p r e s s e d as m e a n values - SEM. t N u m b e r s in p a r e n t h e s e s refer to the n u m b e r o f patients studied. SP < 0.05 for increase above basal. w < 0.05 for difference with recurrent pancreatitis and controls.
The test meal consisted of two eggs (120 g), two pieces of white toast (40 g) with butter (10 g), fruit juice (150 ml) and a cup of coffee with milk (25 g), cereal (24 g), and sugar (6 g) with a total volume of 550 ml and approximately 700 calories. Blood samples for PP concentration were taken before the meal and at 15, 30, 60, and 120 rain after the meal. Radioimmunoassay. Serum PP concentration was measured by radioimmunoassay according to methods previously described (7). Antihuman PP antisera, human PP standards, and bovine PP for labeling were the generous gifts of Drs. R.A. Chance and T.M. Lin, Eli Lilly and Company, Indianapolis, Indiana. Results are expressed as mean -+ SEM. Differences between mean values were determined by paired and unpaired student's t test. RESULTS Basal plasma PP levels in controls (30 - 5 pM), and recurrent pancreatitis patients (39 --+ 12 pM) were similar while chronic pancreatitis patients had lower PP levels (21 --- 9 pM) but this difference did not reach statistical significance. After the meal there was a significant increase of plasma PP (App) in both the controls (P < 0.01) and recurrent pancreatitis patients (P < 0.05) (Table 1). By contrast the meal did not cause a significant increment in plasma PP in chronic pancreatitis patients. The lowest PP increment in response to the meal, observed among the control subjects, was 26 pM. Only three of 11 patients with recurrent pancreatitis had similar or lower App (Figure 1). In contrast 76% (22/29) of the chronic pancreatitis patients had a PP increment lower than the lowest value in controls. No correlation could be established between App and pancreatic e n z y m e secretion in duodenal aspirate in those patients who had the secretin-CCK test (Figure 2). Patients with chronic pancreatitis in general had Digestive Diseases and Sciences, Vol. 24, No. 11 (November 1979)
low App and pancreatic e n z y m e secretion. However, three patients with recurrent pancreatitis secreted pancreatic enzymes at normal rate levels but had low App values. Chronic pancreatitis patients with diabetes had lower App (26.9 --- I4.6 pM) than those without diabetes (44.6 -+ 13.5 pM), but this difference did not reach the level of significance. H o w e v e r , the 13 patients with pancreatic calcifications had a significantly lower App (16.8 +- 4.6 pM) than patients without calcifications (54.1 -- 17.7 pM) (P < 0.05). DISCUSSION Although diabetes mellitus is the major endocrine manifestation of chronic pancreatitis, it usually occurs late in the course of the disease. The late presentation o f insulin deficiency is not unexpected as the cells are protected from destruction by having a central position within the islets of Langerhans. In contrast PP cells are found on the periphery of the islets scattered in the acini and in the epithelium lining the pancreatic ducts. As the PP cell is distributed within both exocrine and endocrine pancreas (5), one might expect a diminished PP response to a meal to be an early sign of pancreatic insufficiency. In the present study we found that the PP response to food was significantly lower in a group o f patients with chronic pancreatitis when compared to that seen in normal subjects or in patients with recurrent pancreatitis. These results are in agreement with those of Adrian et al (8) and Sive et al (9). H o w e v e r , not all the patients with chronic pancreatitis had abnormal PP levels after a meal. Thus 7 of 29 patients with well-documented chronic pancreatitis had increments in plasma PP concentra-
~; 500 Q.
400 E o 300
~, 20o
|. n- 100
MD, I A N L. T A Y L O R , MD, and J O H N H. W A L S H , M D
We studied the plasma pancreatic polypeptide (PP) response to a meal in patients with pancreatitis and attempted to correlate the PP increment with the degree of pancreatic exocrine insufficiency. Control subjects and patients with recurrent pancreatitis showed significant mean increase (P < 0.05) in plasma PP concentration in response to food. By contrast chronic pancreatitis patients had no significant increase in plasma PP. However, some subjects with normal pancreatic secretion had no response and some patients with chronic pancreatitis did show a response. In addition, no correlation was observed between the PP response and pancreatic exocrine secretion. We conclude that the PP response to a meal has only limited value in the detection of pancreatic destruction.
Pancreatic polypeptide (PP) is a peptide o f 36 amino acid residues which was initially discovered as an apparent c o n t a m i n a n t in chicken and bovine insulins (1-3). As the name suggests PP is found alm o s t exclusively in the p a n c r e a s within which its cell of origin has a unique distribution (4). Unlike other pancreatic endocrine cells, the PP cell is not restricted to the islets of L a n g e r h a n s but is found scattered in the p a r e n c h y m a of the exocrine pancreas and in the epithelium of the pancreatic ducts (5). Total p a n c r e a t e c t o m y abolishes the increase in circulating PP seen after a meal (4), suggesting that loss of the PP r e s p o n s e to food might be anticipated in patients with pancreatic destruction s e c o n d a r y to chronic pancreatitis. The p u r p o s e o f the present study was to determine the characteristics of the PP response to a meal in patients with different stages of pancreatitis and to determine w h e t h e r the PP response to food could be correlated with the impairm e n t of exocrine pancreatic secretion.
Manuscript received April 17, 1979; revised manuscript received June 25, 1979; accepted June 29, 1979. From the Gastroenterology Division, University of Southern California and VA Wadsworth Hospital Center, Los Angeles, California. Address for reprint requests: Dr. J.E. Valenzuela, Gastroenterology Division, USC Medical School, 2025 Zonal Avenue, Los Angeles, California 90033.
862
M A T E R I A L S AND M E T H O D S This investigation was approved by the Los Angeles County-University of Southern California Human Research Committee (#01075) and each of the subjects gave informed consent. Twenty-nine patients (22 male and 7 female; mean age 49; range 30-79 years) had chronic alcoholic pancreatitis diagnosed by clinical history of recurrent pancreatitis in all, presence of pancreatic calcification on abdominal radiography (13/29), gross abnormalities of the pancreatic ductal system by endoscopic retrograde pancreatography (16/16), abnormal blood sugar levels (15/29), and steatorrhea (23/29). In addition 16 of the 29 patients had secretin-cholecystokinin test that showed low bicarbonate concentration and decreased pancreatic trypsin (6) secretion suggestive of chronic pancreatitis in all of them. All patients had either pancreatic calcifications and/or abnormal ducts on ERCP and/or exocrine insufficiency on duodenal aspiration. None of the patients had symptoms of acute pancreatitis at the time of the study. Eleven patients (7 male and 4 female; mean age 47; range 19-71 years) were diagnosed as having recurrent pancreatitis by clinical history of at least two well-documented episodes of acute pancreatitis but without presence of radiological abnormalities of the pancreas, normal blood sugar, absence of steatorrhea and normal response to secretin-cholecystokinin stimulation in the four patients in whom this study was performed. Nine of these subjects were chronic alcoholics and two had associated biliary tract disease. Twenty-one subjects (14 males, 7 females; mean age 41 years; range 31-70 years) free of gastrointestinal or other medical disease served as controls. Digestive Diseases and Sciences, Vol. 24, No. 11 (November 1979)
0163-2116/79/1100-0862503.00/1 9 1979DigestiveDisease Systems, Inc.
PANCREATIC POLYPEPTIDE IN PANCREATITIS TABLE 1. EFFECT OF A MEAL ON PLASMA PANCREATIC POLYPEPTIDE (PIcOMOLES PER LITER) IN NORMAL SUBJECTS AND PATIENTS WITH PANCREATITIS*
PP
Controls(21)t Recurrent pancreatitis (11) Chronic pancreatitis(29)
Age
Male~ female
Response to food (A)
47 --- 5
2:1
30 -
5
175 --- 35~
47 --- 4
2:1
39 +- 12
139 --- 48:~
49 - 6
3:1
21 --- 9
36 --- 5w
Basal
*Results are e x p r e s s e d as m e a n values - SEM. t N u m b e r s in p a r e n t h e s e s refer to the n u m b e r o f patients studied. SP < 0.05 for increase above basal. w < 0.05 for difference with recurrent pancreatitis and controls.
The test meal consisted of two eggs (120 g), two pieces of white toast (40 g) with butter (10 g), fruit juice (150 ml) and a cup of coffee with milk (25 g), cereal (24 g), and sugar (6 g) with a total volume of 550 ml and approximately 700 calories. Blood samples for PP concentration were taken before the meal and at 15, 30, 60, and 120 rain after the meal. Radioimmunoassay. Serum PP concentration was measured by radioimmunoassay according to methods previously described (7). Antihuman PP antisera, human PP standards, and bovine PP for labeling were the generous gifts of Drs. R.A. Chance and T.M. Lin, Eli Lilly and Company, Indianapolis, Indiana. Results are expressed as mean -+ SEM. Differences between mean values were determined by paired and unpaired student's t test. RESULTS Basal plasma PP levels in controls (30 - 5 pM), and recurrent pancreatitis patients (39 --+ 12 pM) were similar while chronic pancreatitis patients had lower PP levels (21 --- 9 pM) but this difference did not reach statistical significance. After the meal there was a significant increase of plasma PP (App) in both the controls (P < 0.01) and recurrent pancreatitis patients (P < 0.05) (Table 1). By contrast the meal did not cause a significant increment in plasma PP in chronic pancreatitis patients. The lowest PP increment in response to the meal, observed among the control subjects, was 26 pM. Only three of 11 patients with recurrent pancreatitis had similar or lower App (Figure 1). In contrast 76% (22/29) of the chronic pancreatitis patients had a PP increment lower than the lowest value in controls. No correlation could be established between App and pancreatic e n z y m e secretion in duodenal aspirate in those patients who had the secretin-CCK test (Figure 2). Patients with chronic pancreatitis in general had Digestive Diseases and Sciences, Vol. 24, No. 11 (November 1979)
low App and pancreatic e n z y m e secretion. However, three patients with recurrent pancreatitis secreted pancreatic enzymes at normal rate levels but had low App values. Chronic pancreatitis patients with diabetes had lower App (26.9 --- I4.6 pM) than those without diabetes (44.6 -+ 13.5 pM), but this difference did not reach the level of significance. H o w e v e r , the 13 patients with pancreatic calcifications had a significantly lower App (16.8 +- 4.6 pM) than patients without calcifications (54.1 -- 17.7 pM) (P < 0.05). DISCUSSION Although diabetes mellitus is the major endocrine manifestation of chronic pancreatitis, it usually occurs late in the course of the disease. The late presentation o f insulin deficiency is not unexpected as the cells are protected from destruction by having a central position within the islets of Langerhans. In contrast PP cells are found on the periphery of the islets scattered in the acini and in the epithelium lining the pancreatic ducts. As the PP cell is distributed within both exocrine and endocrine pancreas (5), one might expect a diminished PP response to a meal to be an early sign of pancreatic insufficiency. In the present study we found that the PP response to food was significantly lower in a group o f patients with chronic pancreatitis when compared to that seen in normal subjects or in patients with recurrent pancreatitis. These results are in agreement with those of Adrian et al (8) and Sive et al (9). H o w e v e r , not all the patients with chronic pancreatitis had abnormal PP levels after a meal. Thus 7 of 29 patients with well-documented chronic pancreatitis had increments in plasma PP concentra-
~; 500 Q.
400 E o 300
~, 20o
|. n- 100
