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Timing of emergency ERCP and treatment procedures in acute biliary pancreatitis
A398
AGA ABSTRACTS
TIMING OF EMERGENCY ERCP AND TREATMENT PROCEDURES IN ACUTE BILIARY PANCREATITIS. W. Veltzke, A. Adler, K.E. Hampel, R.E Hintze. Central !nterdisciplinary Endoscopy, Dept. of Gastroenterology, University Hospital Rudolf Virchow, Free University of Berlin, Germany Introduction: Indication for ERC and eventually endoscopic sphincterotomy (EST) in acute biliary panereatitis is undisputed today. Timing for an eventual intervention is discussed controversially. We evaluated in this study the significance of an emergency ERC/EST for the outcome in patients with such diagnosis. Methods: There were two therapeutic options: In group A with biliary pancreatitis an emergency ERC/EST was performed within 4 hours after admission to our hospital. In group B the therapy followed after an 24 up to 36 hours interval in the regular daily working time. The time interval from the beginning of the typical symptoms up to the admission to hospital was registered. The total patient number was n = 25, in group A n = 13, in group B n =12, mean age: 58,3 years, n = 17 female, n = 8 male, in both groups sex and age paired. Follow-up treatment was due to the standard in internal medicine with intensive care, antibiotics and infusion therapy. Results: The time interval between the biliary induction until the admission to hospital was in groups possible at every time. It was performed in group A in 1.6 days, in group B 1.9 days in the mean. An ERC/EST also under emergency conditions was in both group A in 68.5 % of the cases out of the regular working time. Clinical diagnosis was proved in all cases by the result of ERC. In group A lipasaemia was normalized after 5.2 days, lenkocytosis after 5.6 days. I n group B the serum-lipase level was in the normal range after 14.0 days, leukocytosis after 7.3 days. In two cases in group B a severe septic cholangitis occured. There were no complications Due to the therapeutic procedures or the pancreatitis, and no fatal outcome. Conclusions: Up to this time the therapeut!c groups ai'e to small to make statistically significant statements but there is a clear trend to a mild course of the disease in cases of emergency endoscopic interventions. If an emergency-ERC-team should be present around the clock also considering the economic implications is to be discussed with the shorter stay in hospital and the saved intensive care days.
• AZATHIOPRINE DEPLETES PANCREATIC GLUTATHIONE AND INDUCES GAMMA-GLUTAMYLCYSTEINE SYNTHETASE ACTIVITY. H.A. Villarreal, L.D. Wells, B.A. Neuschwander-Tetri. Division of Gastroenterology and Hepatology, Saint Louis University Health Sciences Center, St. Louis, MO. Glutathione is a major antioxidant at the cellular level and has been shown to be protective in one model of experimental pancreatitis (J Clin Invest 8 9 : 1 0 9 , 1992), Prior studies have demonstrated hepatic glutathione depletion in rats treated with azathioprine. The effect of acute administration of azathioprine on pancreatic glutathione is unknown. The purpose of these experiments was to determine if azathioprine alters pancreatic glutathione levels or synthetic capacity. Methods: 12-15 g female Swiss-Webster mice were fasted overnight and treated with azathioprine as a single 0.1 ml intraperitoneal injection of a 0 . 1 5 M solution (pH 9-10~ 1 0 0 0 p m o l / k g ) . Lesser doses were delivered as diluted solutions in the same volume. The pancreata were rapidly excised and frozen in liquid nitrogen. Glutathione (total, GSH + acid soluble GSSX) was determined by HPLC. y-Glutamylcysteine synthetase activity (GCS) was measured in pancreatic homogenate containing protease inhibitors by incubating w i t h 0.1 mM eysteine, glutamic acid and ATP and measuring newly synthesized I/glutamylcysteine by HPLC. Results: Azatbioprine depleted pancreatic glutathione and induced GCS activity in a time (after l O 0 0 p g / k g ) and dose (at 3 hr) dependent manner. Hours 0 3 6 12 GSH (/Imol/g) 1.93±0.08 0.43±0~07" 1.60±0.24 2.65±0.09* GCS (U/ragprotein} 0.62±0,04 1.93±0.12 2.51 ±0.33 2.46±0.15 Azathioprine, pmol/kg 0 100 316 1000 GSH (pmol/g) 1.93±0.08 2.02±0,06 1.96±0.14 0.40±0.04* COS (U/rugprotein) 1.11 ±0.14 1.03±0.14 1.34-+0.10 3,00±0,55* *P
GASTROENTEROLOGY, VOl. 1 0 8 , NO. 4
• IMMUNOLOCAI,IZATION OF F I B R O B L A S T GROWTH FACTORS AND HIGH AFFINITY RECEPTORS IN PANCREATIC ADENOCARCINOMAS. S. Vickers. R. Crowe, T. Smoot, M. Gutierrez, K. Luo, Q. Ding, J. Aldrete, J[.A. Thompson. Department of Sttrgery, Pathology, and Biostatistics. University of Alabama at Birmingham. The prototypic members of the fibroblast growth factor (FGF) gene family are welt recognized as initiators of angiogenesis, a process which has been demonstrated both to precede tumorigenesis and to reflect the transition from hyperplasia to neoplasia. In particular, both FGF- 1 (acidic) and FGF-2 (basic) may contribute to tumor proliferation, angiogenesis, and metastasis. In this present study, we examined 35 pancreatic adenocarcinomas and 4 normal pancreases (transplant donors) for the expression of FGF-1, 'FGF-2, and the high affinity FGF receptors (FGFR- 1 and FGFR-2) using both immuaohistochemical and hybridization techniques in situ. Our results demonstrated that 75% of the tumors examined demonstrated the exaggerated appearance (3+ to 4+) of immunoreactive FGF-1, FGF-2, FGFR-1, and FGFR-2 associated with ductal cancer cells, particularly those surrounding microvasculature interstitium and islet cells. There was minimal to no (0 to 1+) gaining for these ligands and receptors in the normal exocrine pancreas; however, intense immunostaining (3+) for FGFR-1 and FGFR-2 was noted in islet cells. In situ hybridization studies demonstrated that the increased appearance of the polypeptide growth factor was accompanied by strong staining (4+) for FGF mRNA in both the malignant duetal cell microvasculature and nonmalignant acinar cells. Normal pancreatic tissue demonstrated minimal to no :staining (0 to 1+) for FGF mRNA. Collectively, these data suggest that fibroblast growth factors and their receptors may have an important role in progression of pancreatic exocrine tumor formation and accompanying angiogenic processes.
AZATHIOPRINE-INDUCED ACUTE PANCREATITIS IN MICE. H.A. Viilarreal, L.D. Wells. B.A. Neuschwander-Tetri. Division of Gastroenterology and Hepatology, Saint Louis University Health Sciences Center, St. Louis, MO. Azathioprme causes acute pancreatitis in 5-6% of patients treated with this drug. The mechanisms of azathioprine-induced pancreatic injury are not understood and animal models of azathioprineinduced acute Dancreatitis have not been described. The purpose of these experiments was to determine if azathioprine causes acute pancreatitis in mice. Methods 12-15 g female Swiss-Webster mice were fasted overnight. Water was administered ad lib. Mice were treated with azathioprine as a single 0.1 ml intraperitoneal injection of a 0.15 M solution (oH 9-10; 1000 /Jmol/kg). Lesser doses were delivered as diluted solutions in the same volume. After defined time periods, mice were sacrificed by carbon dioxide inhalation. Mixed arteriovenous blood obtained by decapitation was mixed w i t h heparlr and plasma was isolated by centrifugation. Amylase activity was determined using the Phadebas reagent. The pancreata were excised. fixed in formalin and stained with hematoxylin and eosin for histopathological evaluation. F%sults Azathioprine caused dose (at 6 hr) and time dependent (after 1000 pg/kg) elevations of the plasma amylase (U/ml): Hours 0 6 12 24 Amylase 6.1 16.6" 12.6" 6.7 Std Err (1.1) (3.6) (2.1) (1.3) Azathioprine, pg/kg 0 10 32 100 316 1000 Amylase 5,32 3.70 5.16 7.02* 9.60* 7.80* Std Err (0.36) (0.65) (0.56) (0.23) (1.55) (0.78) *P<0.05 comDarea to control. Histological evidence of pancreatitis was evident after 9 and 1 2 hr in mice treated with 1000pg/kg azathioprine. Histologic findings included acinar cell vacuolization, increase mitotic activity and the presence of perivascular and intralobular inflammatory cells. Glycine, 0.1 5 M, pH 10, did not increase the serum amylase or cause histological changes. Conclusions: High dose azathioprine caused biochemical and histological evidence of acute pancreatitis. This model may represent a new and clinically relevant model of drug-induced acute pancreatitis.
AGA ABSTRACTS
TIMING OF EMERGENCY ERCP AND TREATMENT PROCEDURES IN ACUTE BILIARY PANCREATITIS. W. Veltzke, A. Adler, K.E. Hampel, R.E Hintze. Central !nterdisciplinary Endoscopy, Dept. of Gastroenterology, University Hospital Rudolf Virchow, Free University of Berlin, Germany Introduction: Indication for ERC and eventually endoscopic sphincterotomy (EST) in acute biliary panereatitis is undisputed today. Timing for an eventual intervention is discussed controversially. We evaluated in this study the significance of an emergency ERC/EST for the outcome in patients with such diagnosis. Methods: There were two therapeutic options: In group A with biliary pancreatitis an emergency ERC/EST was performed within 4 hours after admission to our hospital. In group B the therapy followed after an 24 up to 36 hours interval in the regular daily working time. The time interval from the beginning of the typical symptoms up to the admission to hospital was registered. The total patient number was n = 25, in group A n = 13, in group B n =12, mean age: 58,3 years, n = 17 female, n = 8 male, in both groups sex and age paired. Follow-up treatment was due to the standard in internal medicine with intensive care, antibiotics and infusion therapy. Results: The time interval between the biliary induction until the admission to hospital was in groups possible at every time. It was performed in group A in 1.6 days, in group B 1.9 days in the mean. An ERC/EST also under emergency conditions was in both group A in 68.5 % of the cases out of the regular working time. Clinical diagnosis was proved in all cases by the result of ERC. In group A lipasaemia was normalized after 5.2 days, lenkocytosis after 5.6 days. I n group B the serum-lipase level was in the normal range after 14.0 days, leukocytosis after 7.3 days. In two cases in group B a severe septic cholangitis occured. There were no complications Due to the therapeutic procedures or the pancreatitis, and no fatal outcome. Conclusions: Up to this time the therapeut!c groups ai'e to small to make statistically significant statements but there is a clear trend to a mild course of the disease in cases of emergency endoscopic interventions. If an emergency-ERC-team should be present around the clock also considering the economic implications is to be discussed with the shorter stay in hospital and the saved intensive care days.
• AZATHIOPRINE DEPLETES PANCREATIC GLUTATHIONE AND INDUCES GAMMA-GLUTAMYLCYSTEINE SYNTHETASE ACTIVITY. H.A. Villarreal, L.D. Wells, B.A. Neuschwander-Tetri. Division of Gastroenterology and Hepatology, Saint Louis University Health Sciences Center, St. Louis, MO. Glutathione is a major antioxidant at the cellular level and has been shown to be protective in one model of experimental pancreatitis (J Clin Invest 8 9 : 1 0 9 , 1992), Prior studies have demonstrated hepatic glutathione depletion in rats treated with azathioprine. The effect of acute administration of azathioprine on pancreatic glutathione is unknown. The purpose of these experiments was to determine if azathioprine alters pancreatic glutathione levels or synthetic capacity. Methods: 12-15 g female Swiss-Webster mice were fasted overnight and treated with azathioprine as a single 0.1 ml intraperitoneal injection of a 0 . 1 5 M solution (pH 9-10~ 1 0 0 0 p m o l / k g ) . Lesser doses were delivered as diluted solutions in the same volume. The pancreata were rapidly excised and frozen in liquid nitrogen. Glutathione (total, GSH + acid soluble GSSX) was determined by HPLC. y-Glutamylcysteine synthetase activity (GCS) was measured in pancreatic homogenate containing protease inhibitors by incubating w i t h 0.1 mM eysteine, glutamic acid and ATP and measuring newly synthesized I/glutamylcysteine by HPLC. Results: Azatbioprine depleted pancreatic glutathione and induced GCS activity in a time (after l O 0 0 p g / k g ) and dose (at 3 hr) dependent manner. Hours 0 3 6 12 GSH (/Imol/g) 1.93±0.08 0.43±0~07" 1.60±0.24 2.65±0.09* GCS (U/ragprotein} 0.62±0,04 1.93±0.12 2.51 ±0.33 2.46±0.15 Azathioprine, pmol/kg 0 100 316 1000 GSH (pmol/g) 1.93±0.08 2.02±0,06 1.96±0.14 0.40±0.04* COS (U/rugprotein) 1.11 ±0.14 1.03±0.14 1.34-+0.10 3,00±0,55* *P
GASTROENTEROLOGY, VOl. 1 0 8 , NO. 4
• IMMUNOLOCAI,IZATION OF F I B R O B L A S T GROWTH FACTORS AND HIGH AFFINITY RECEPTORS IN PANCREATIC ADENOCARCINOMAS. S. Vickers. R. Crowe, T. Smoot, M. Gutierrez, K. Luo, Q. Ding, J. Aldrete, J[.A. Thompson. Department of Sttrgery, Pathology, and Biostatistics. University of Alabama at Birmingham. The prototypic members of the fibroblast growth factor (FGF) gene family are welt recognized as initiators of angiogenesis, a process which has been demonstrated both to precede tumorigenesis and to reflect the transition from hyperplasia to neoplasia. In particular, both FGF- 1 (acidic) and FGF-2 (basic) may contribute to tumor proliferation, angiogenesis, and metastasis. In this present study, we examined 35 pancreatic adenocarcinomas and 4 normal pancreases (transplant donors) for the expression of FGF-1, 'FGF-2, and the high affinity FGF receptors (FGFR- 1 and FGFR-2) using both immuaohistochemical and hybridization techniques in situ. Our results demonstrated that 75% of the tumors examined demonstrated the exaggerated appearance (3+ to 4+) of immunoreactive FGF-1, FGF-2, FGFR-1, and FGFR-2 associated with ductal cancer cells, particularly those surrounding microvasculature interstitium and islet cells. There was minimal to no (0 to 1+) gaining for these ligands and receptors in the normal exocrine pancreas; however, intense immunostaining (3+) for FGFR-1 and FGFR-2 was noted in islet cells. In situ hybridization studies demonstrated that the increased appearance of the polypeptide growth factor was accompanied by strong staining (4+) for FGF mRNA in both the malignant duetal cell microvasculature and nonmalignant acinar cells. Normal pancreatic tissue demonstrated minimal to no :staining (0 to 1+) for FGF mRNA. Collectively, these data suggest that fibroblast growth factors and their receptors may have an important role in progression of pancreatic exocrine tumor formation and accompanying angiogenic processes.
AZATHIOPRINE-INDUCED ACUTE PANCREATITIS IN MICE. H.A. Viilarreal, L.D. Wells. B.A. Neuschwander-Tetri. Division of Gastroenterology and Hepatology, Saint Louis University Health Sciences Center, St. Louis, MO. Azathioprme causes acute pancreatitis in 5-6% of patients treated with this drug. The mechanisms of azathioprine-induced pancreatic injury are not understood and animal models of azathioprineinduced acute Dancreatitis have not been described. The purpose of these experiments was to determine if azathioprine causes acute pancreatitis in mice. Methods 12-15 g female Swiss-Webster mice were fasted overnight. Water was administered ad lib. Mice were treated with azathioprine as a single 0.1 ml intraperitoneal injection of a 0.15 M solution (oH 9-10; 1000 /Jmol/kg). Lesser doses were delivered as diluted solutions in the same volume. After defined time periods, mice were sacrificed by carbon dioxide inhalation. Mixed arteriovenous blood obtained by decapitation was mixed w i t h heparlr and plasma was isolated by centrifugation. Amylase activity was determined using the Phadebas reagent. The pancreata were excised. fixed in formalin and stained with hematoxylin and eosin for histopathological evaluation. F%sults Azathioprine caused dose (at 6 hr) and time dependent (after 1000 pg/kg) elevations of the plasma amylase (U/ml): Hours 0 6 12 24 Amylase 6.1 16.6" 12.6" 6.7 Std Err (1.1) (3.6) (2.1) (1.3) Azathioprine, pg/kg 0 10 32 100 316 1000 Amylase 5,32 3.70 5.16 7.02* 9.60* 7.80* Std Err (0.36) (0.65) (0.56) (0.23) (1.55) (0.78) *P<0.05 comDarea to control. Histological evidence of pancreatitis was evident after 9 and 1 2 hr in mice treated with 1000pg/kg azathioprine. Histologic findings included acinar cell vacuolization, increase mitotic activity and the presence of perivascular and intralobular inflammatory cells. Glycine, 0.1 5 M, pH 10, did not increase the serum amylase or cause histological changes. Conclusions: High dose azathioprine caused biochemical and histological evidence of acute pancreatitis. This model may represent a new and clinically relevant model of drug-induced acute pancreatitis.