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Clinical evaluation of faecal elastase 1 (E1) as an exocrine function test in the diagnosis of chronic pancreatitis
April 1998
P a n c r e a t i c D i s o r d e r s A447
(n=26) were studied. SO manometric activity and blood pressure were continuously monitored and serum collected hourly for amylase estimation. The first group of experiments comprised: sham operation (n=5); PD ligation (fixed PD obstruction) alone (n=4); PD ligation + secretin (n=4); PD ligation + cholecystokinin-octapeptide (CCK) + secretin (n=5); PD decompression + CCK + secretin (n=4). In 3 other groups, the SO received multiple applications of topical carbachol (carbamylcholine) (total: 417 +- 179 nmoles) to produce SO hyperactivity resulting in PD obstruction for 5 hours: carbachol alone (n=6); carbachol + PD decompression; carbachol + CCK + secretin (n=4). CCK and secretin were given as graded intravenous boluses 0.5-51ag/kg (each), half hourly. On completion, animals were euthanased and the pancreas harvested for histological diagnosis of pancreatitis using a scoring system. Statistical analysis utilized ANOVA and repeated measures ANOVA. RESULTS: Sham, PD ligation alone and PD decompressed groups were not associated with hyperamylasaemia. Fixed or carbachol stimulated transient PD obstruction plus stimulated pancreatic exocrine secretion was associated with 1.4-2.4 fold increase in amylase (P < 0.05) and a higher histological score for pancreatitis (P < 0.05). These effects were not seen if the PD was decompressed. 3** J . . . . . . . . .
1 ~ "L- ~ " ~
i .................
- ' l I Z 7 - ~- -
,T [ : 0
1
2
+[--~.e.,~,vcc~
-:-. ~.-- .Z.. -...TI...,,~d~,,,,,~,,
.ST,ST 3
4 $ Time (ho~rs)
6
L
7
8
CONCLUSION: Transient PD obstruction by increased SO activity, in conjunction with elevated pancreatic exocrine secretion induces AP. This possum model is appropriate for the study of early pancreatitis secondary to SO dysfunction and biliary pancreatitis. The support of the National Health and Medical Research Council of Australia and the National Parks and Wildlife Service are acknowledged. • G1817 CLINICAL EVALUATION OF FAECAL ELASTASE 1 (El) AS AN EXOCRINE FUNCTION TEST IN THE DIAGNOSIS OF CHRONIC PANCREATITIS. H.S. Choi, J.S. Ham, D.S. Hart, J.H. Son, Y.C. Jun, O.Y. Lee, B.C. Yoon, M.H. Lee, C.S. Kee, K.N. Park. Department of Internal Medicine, Hanyang University Hospital, Seoul, Korea Quantitative determination of fecal elastase I(E1) has been proposed as a noninvasive test of exocrine pancreatic function. The purpose of this study was to evaluate cut-off value of fecal E1 in healthy control, control patient, chronic pancreatitis and to evaluate the sensitivity and specificity of fecal E1 in chronic pancreatitis compared with intraductal secretin test (IDST) as "gold standard". Methods: E1 concentrations were measured in spot stool samples of 40 healthy controls, 21 control patients with alcoholic liver disease and 12 patients with chronic pancreatitis (ELISA; SchBo. Tech, Germany). IDST was performed during ERCP; pancreatic juice (PJ) was collected by manual suction with a 10-ml syringe at 5-min interval for 15-rain after a bolus intravenous injection of I00 units secretin (Secrepan; Eisai, Tokyo, Japan). The cut-off value of fecal E1 was calculated with Receiver Operating Curve (Epistat), results of IDST were evaluated based on six parameters; PJ volume (ml), bicarbonate concentration (meq/L), bicarbonate output (meq), pancreatic juice E1 (lag/ml), amylase output (U/ml), lipase output (U/ml). The sensitivity and specificity of E1 were compared with the results of IDST. Various correlations between fecal E1 and results of IDST were performed. Results: Fecal E1 concentration (196 +-268.32 pg/g stool) in patients with chronic pancreatitis were significantly lower compared with health control (815 + 843 lag/g stool) or control patients (594 ± 943 pg/g stool)(p < 0.01). The cut-off value of fecal E1 to discriminate between healthy control and chronic pancreatitis was 201 pg/g stool. E1 concentration below 2011ag/g stool show that total sensitivity, specificity and accuracy of chronic pancreatitis were respectively 67.7%, 82.5%, 78.8% and sensitivity for moderate and severe chronic pancreatitis was 77.8%, whereas sensitivity for mild chronic pancreatitis was 33.3%. Significant correlation between fecal E1 and parameters of IDST were found (pancreatic juice volume; r=0.8, bicarbonate concentration; r=-0.85, bicarbonate output; r=0.8, pancreatic juice elastase; r=0.67, amylase output; r=0.783)(p <0.02), Conclusion: The diagnostic sensitivity of fecal E1 for moderate and severe chronic pancreatitis was excellent and for mild chronic pancreatitis was limited, but significant correlation between fecal E1 and IDST as seen. Therefore fecal El proved to be a highly sensitive and specific exocrine function test in chronic pancreatitis.
G1818
SIGNIFICANCE OF HETEROZYGOUS CYSTIC FIBROSIS GENE (CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR" MUTATIONS) IN IDIOPATHIC PANCREATITIS. CP Choudari, AC Yu, TF Imperiale, EL Fogel, S Sherman, GA Lehman. Indiana University Medical Center, Indianapolis, IN. Between 5-15% of patients with recurrent pancreatitis have no identified etiology after routine investigations and advanced endoscopic evaluation. The majority of the patients with cystic fibrosis (CF) homozygous disease suffer from chronic pancreatitis and pancreatic insufficiency. This study evaluated whether idiopathic pancreatitis is associated with the heterozygous state of CF. M e t h o d s : Two hundred twenty five patients with pancreatitis and 210 controls (patients without pancreatitis) undergoing ERCP were tested for 13 CF-causing CFTR mutations by DNA probe analysis. Sixty four patients had a known cause for pancreatitis (excess alcohol intake in 39; gallstone in 15; hypertriglyceridemia in 4; hereditary pancreatitis in 5; and trauma in one patient). Fifty-one patients had a potential cause for pancreatitis after endoscopic evaluation (pancreas divisum in 38; tumor in 9; anomalous pancreatobiliary junction in 3; and choledochal cyst in one), Six patients with homozygous cystic fibrosis were excluded. The remaining 104 patients with "idiopathic pancreatitis" (IP) were compared to 210 control patients. Results: The frequency of CFfR mutations(heterozygous) were: IP Controls P. divisum n=104 n=210' n=38 Caucasians 19/96 7/198 8/37 Afro-Amer 0/4 0/12 -Asian 0/4 -0/1 Total 19/104 7/210 8/38
EtOH n=39 2/31 0/8 -2/39
Miscellaneous n=38 0/36 0/1 0/1 0/38
Nineteen Caucasian patients (19%) with IP were heterozygotes (carried a single CFTR mutation) compared to the local population carrier rate of 3.53% (p < 0.00001). Patients with IP have a relative odds of carrying a CFTR mutation of 6.7 (95% CI 2.8-16.3). Twenty-one percent (8/38) of patients with pancreas divisum were also heterozygotes (p <0.0001). In heterozygotes, sweat chlorides were normal in all tested patients (n=7). Summary: Caucasian idiopathic pancreatitis patients have a statistically significant increase in CF heterozygous frequency. Conclusions: The heterozygous state of the CF gene appears to predispose Caucasians to pancreatitis probably by defective CFTR chloride function in the pancreatic duct similar to the homozygous state. (;1519 YIELD OF GENETIC TESTING IN PANCREATIC DISEASE AS WE KNOW IT IN 1997. CP Choudari; T Stewart, D Crabb, EL Fogel, S Sherman, GL Lehman. Indiana University Medical Center, Indianapolis, IN. Increasing attention has been directed towards identifying genetic alterations in the pathogenesis of common disorders. This study examined the prevalence of three genetic mutations in pancreatic disease and their potential role in pathogenesis of disease. M e t h o d s : Between 8/97 - 11/97, 102 consecutive patients with pancreatic disease undergoing ERCP were tested for 13 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations for Cystic Fibrosis (CF), alpha-1antitrypsin (A1AT) phenotypes, and the Hereditary pancreatitis (HP) cationic trypsinogen gene. The pancreatic diseases evaluated were idiopathic pancreatitis (IP) in 55, alcoholic pancreatitis in 9, gallstone pancreatitis(GSP) in 6, pancreas divisum with recurrent pancrealitis in 20, and pancreatic tumor in 12. Results: The frequency of genetic mutations were as follows: Pancreatic disease IP (55) EtOH (9) P. Divisum (20) GSP (6) Tumor (12) Total (102)
CFFR mutations hetero 5 0 1 0 0 6
AIAT phenotypes homo hertero* 1 4 0 1 0 1 0 0 0 0 1 6
HP gene 2 0 0 0 0 2
Genetic mutation % 12/55 (21%) 1/9 (11%) 2/20 (10%) 0/6 (0%) 0/12 (0%) 15/102(15%)
Fifteen percent of patients with pancreatic disease had a genetic mutation; 6% had a CFTR mutation, 7% had an abnormal alpha-l-antitrypsin phenotype, and 2% had HP gene. "3/6 had low alpha-1-antitrypsin serum levels. Summary: In this series of patients with pancreatic disorders undergoing ERCP, 15% had a genetic mutation. C o n c l u s i o n s : Although pancreatic involvement is well recognized in patients with Hereditary Pancreatitis and Cystic Fibrosis, the role of the heterozygous state of CF and abnormal alpha-l-antitrypsin phenotypes (with deficiency in A1AT levels) in predisposing individuals to disease is less clear. Noninvasive evaluation of IP should include CF and HP gene testing.
P a n c r e a t i c D i s o r d e r s A447
(n=26) were studied. SO manometric activity and blood pressure were continuously monitored and serum collected hourly for amylase estimation. The first group of experiments comprised: sham operation (n=5); PD ligation (fixed PD obstruction) alone (n=4); PD ligation + secretin (n=4); PD ligation + cholecystokinin-octapeptide (CCK) + secretin (n=5); PD decompression + CCK + secretin (n=4). In 3 other groups, the SO received multiple applications of topical carbachol (carbamylcholine) (total: 417 +- 179 nmoles) to produce SO hyperactivity resulting in PD obstruction for 5 hours: carbachol alone (n=6); carbachol + PD decompression; carbachol + CCK + secretin (n=4). CCK and secretin were given as graded intravenous boluses 0.5-51ag/kg (each), half hourly. On completion, animals were euthanased and the pancreas harvested for histological diagnosis of pancreatitis using a scoring system. Statistical analysis utilized ANOVA and repeated measures ANOVA. RESULTS: Sham, PD ligation alone and PD decompressed groups were not associated with hyperamylasaemia. Fixed or carbachol stimulated transient PD obstruction plus stimulated pancreatic exocrine secretion was associated with 1.4-2.4 fold increase in amylase (P < 0.05) and a higher histological score for pancreatitis (P < 0.05). These effects were not seen if the PD was decompressed. 3** J . . . . . . . . .
1 ~ "L- ~ " ~
i .................
- ' l I Z 7 - ~- -
,T [ : 0
1
2
+[--~.e.,~,vcc~
-:-. ~.-- .Z.. -...TI...,,~d~,,,,,~,,
.ST,ST 3
4 $ Time (ho~rs)
6
L
7
8
CONCLUSION: Transient PD obstruction by increased SO activity, in conjunction with elevated pancreatic exocrine secretion induces AP. This possum model is appropriate for the study of early pancreatitis secondary to SO dysfunction and biliary pancreatitis. The support of the National Health and Medical Research Council of Australia and the National Parks and Wildlife Service are acknowledged. • G1817 CLINICAL EVALUATION OF FAECAL ELASTASE 1 (El) AS AN EXOCRINE FUNCTION TEST IN THE DIAGNOSIS OF CHRONIC PANCREATITIS. H.S. Choi, J.S. Ham, D.S. Hart, J.H. Son, Y.C. Jun, O.Y. Lee, B.C. Yoon, M.H. Lee, C.S. Kee, K.N. Park. Department of Internal Medicine, Hanyang University Hospital, Seoul, Korea Quantitative determination of fecal elastase I(E1) has been proposed as a noninvasive test of exocrine pancreatic function. The purpose of this study was to evaluate cut-off value of fecal E1 in healthy control, control patient, chronic pancreatitis and to evaluate the sensitivity and specificity of fecal E1 in chronic pancreatitis compared with intraductal secretin test (IDST) as "gold standard". Methods: E1 concentrations were measured in spot stool samples of 40 healthy controls, 21 control patients with alcoholic liver disease and 12 patients with chronic pancreatitis (ELISA; SchBo. Tech, Germany). IDST was performed during ERCP; pancreatic juice (PJ) was collected by manual suction with a 10-ml syringe at 5-min interval for 15-rain after a bolus intravenous injection of I00 units secretin (Secrepan; Eisai, Tokyo, Japan). The cut-off value of fecal E1 was calculated with Receiver Operating Curve (Epistat), results of IDST were evaluated based on six parameters; PJ volume (ml), bicarbonate concentration (meq/L), bicarbonate output (meq), pancreatic juice E1 (lag/ml), amylase output (U/ml), lipase output (U/ml). The sensitivity and specificity of E1 were compared with the results of IDST. Various correlations between fecal E1 and results of IDST were performed. Results: Fecal E1 concentration (196 +-268.32 pg/g stool) in patients with chronic pancreatitis were significantly lower compared with health control (815 + 843 lag/g stool) or control patients (594 ± 943 pg/g stool)(p < 0.01). The cut-off value of fecal E1 to discriminate between healthy control and chronic pancreatitis was 201 pg/g stool. E1 concentration below 2011ag/g stool show that total sensitivity, specificity and accuracy of chronic pancreatitis were respectively 67.7%, 82.5%, 78.8% and sensitivity for moderate and severe chronic pancreatitis was 77.8%, whereas sensitivity for mild chronic pancreatitis was 33.3%. Significant correlation between fecal E1 and parameters of IDST were found (pancreatic juice volume; r=0.8, bicarbonate concentration; r=-0.85, bicarbonate output; r=0.8, pancreatic juice elastase; r=0.67, amylase output; r=0.783)(p <0.02), Conclusion: The diagnostic sensitivity of fecal E1 for moderate and severe chronic pancreatitis was excellent and for mild chronic pancreatitis was limited, but significant correlation between fecal E1 and IDST as seen. Therefore fecal El proved to be a highly sensitive and specific exocrine function test in chronic pancreatitis.
G1818
SIGNIFICANCE OF HETEROZYGOUS CYSTIC FIBROSIS GENE (CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR" MUTATIONS) IN IDIOPATHIC PANCREATITIS. CP Choudari, AC Yu, TF Imperiale, EL Fogel, S Sherman, GA Lehman. Indiana University Medical Center, Indianapolis, IN. Between 5-15% of patients with recurrent pancreatitis have no identified etiology after routine investigations and advanced endoscopic evaluation. The majority of the patients with cystic fibrosis (CF) homozygous disease suffer from chronic pancreatitis and pancreatic insufficiency. This study evaluated whether idiopathic pancreatitis is associated with the heterozygous state of CF. M e t h o d s : Two hundred twenty five patients with pancreatitis and 210 controls (patients without pancreatitis) undergoing ERCP were tested for 13 CF-causing CFTR mutations by DNA probe analysis. Sixty four patients had a known cause for pancreatitis (excess alcohol intake in 39; gallstone in 15; hypertriglyceridemia in 4; hereditary pancreatitis in 5; and trauma in one patient). Fifty-one patients had a potential cause for pancreatitis after endoscopic evaluation (pancreas divisum in 38; tumor in 9; anomalous pancreatobiliary junction in 3; and choledochal cyst in one), Six patients with homozygous cystic fibrosis were excluded. The remaining 104 patients with "idiopathic pancreatitis" (IP) were compared to 210 control patients. Results: The frequency of CFfR mutations(heterozygous) were: IP Controls P. divisum n=104 n=210' n=38 Caucasians 19/96 7/198 8/37 Afro-Amer 0/4 0/12 -Asian 0/4 -0/1 Total 19/104 7/210 8/38
EtOH n=39 2/31 0/8 -2/39
Miscellaneous n=38 0/36 0/1 0/1 0/38
Nineteen Caucasian patients (19%) with IP were heterozygotes (carried a single CFTR mutation) compared to the local population carrier rate of 3.53% (p < 0.00001). Patients with IP have a relative odds of carrying a CFTR mutation of 6.7 (95% CI 2.8-16.3). Twenty-one percent (8/38) of patients with pancreas divisum were also heterozygotes (p <0.0001). In heterozygotes, sweat chlorides were normal in all tested patients (n=7). Summary: Caucasian idiopathic pancreatitis patients have a statistically significant increase in CF heterozygous frequency. Conclusions: The heterozygous state of the CF gene appears to predispose Caucasians to pancreatitis probably by defective CFTR chloride function in the pancreatic duct similar to the homozygous state. (;1519 YIELD OF GENETIC TESTING IN PANCREATIC DISEASE AS WE KNOW IT IN 1997. CP Choudari; T Stewart, D Crabb, EL Fogel, S Sherman, GL Lehman. Indiana University Medical Center, Indianapolis, IN. Increasing attention has been directed towards identifying genetic alterations in the pathogenesis of common disorders. This study examined the prevalence of three genetic mutations in pancreatic disease and their potential role in pathogenesis of disease. M e t h o d s : Between 8/97 - 11/97, 102 consecutive patients with pancreatic disease undergoing ERCP were tested for 13 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations for Cystic Fibrosis (CF), alpha-1antitrypsin (A1AT) phenotypes, and the Hereditary pancreatitis (HP) cationic trypsinogen gene. The pancreatic diseases evaluated were idiopathic pancreatitis (IP) in 55, alcoholic pancreatitis in 9, gallstone pancreatitis(GSP) in 6, pancreas divisum with recurrent pancrealitis in 20, and pancreatic tumor in 12. Results: The frequency of genetic mutations were as follows: Pancreatic disease IP (55) EtOH (9) P. Divisum (20) GSP (6) Tumor (12) Total (102)
CFFR mutations hetero 5 0 1 0 0 6
AIAT phenotypes homo hertero* 1 4 0 1 0 1 0 0 0 0 1 6
HP gene 2 0 0 0 0 2
Genetic mutation % 12/55 (21%) 1/9 (11%) 2/20 (10%) 0/6 (0%) 0/12 (0%) 15/102(15%)
Fifteen percent of patients with pancreatic disease had a genetic mutation; 6% had a CFTR mutation, 7% had an abnormal alpha-l-antitrypsin phenotype, and 2% had HP gene. "3/6 had low alpha-1-antitrypsin serum levels. Summary: In this series of patients with pancreatic disorders undergoing ERCP, 15% had a genetic mutation. C o n c l u s i o n s : Although pancreatic involvement is well recognized in patients with Hereditary Pancreatitis and Cystic Fibrosis, the role of the heterozygous state of CF and abnormal alpha-l-antitrypsin phenotypes (with deficiency in A1AT levels) in predisposing individuals to disease is less clear. Noninvasive evaluation of IP should include CF and HP gene testing.