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Etiological risk factors for familial pancreatitis
April 2000
lymphocytes were examined by flow cytometry and ELISA. Results: More than one autoantibody was observed in all 20 patients. Serum antinuclear antibody was detected in 15 of 20 patients, anti-LF antibody in 15, anti-CA-II antibody in 12, rheumatoid factor in 7, anti-smooth muscle antibody in 5, but anti-mitochondrial antibody in none. The serum levels of anti-CA-II and LF antibody were not correlated. The ratios of HLADR+CD3+ (30.2±10.7 %), HLA-DR+CD4+ (17.0±4.5 %) and HLADR +CD8+ (25.6±4.8 %) PBLs in AlP (n= 13) were significantly higher than those in control patients (HLA-DR+CD3+, 15.3±3.0 %; HLADR+CD4+, 8.5±1.5 %; HLA-DR+CD8+, 1O.2±3.6 %). CD4+CD45RO+ (33.2±3.3 %) and CD8+CD45RO+ memory cells (22.2±4.9 %) in AlP tended to be increased compared with those in control pancreatitis patients (CD4+CD45RO+, 24.4±3.7 %; CD8 + CD45RO + , 15.8±2.7 %). A flow cytometric analysis of intracellular cytokines showed that the ratios of CD4 positive cells producing IFN-yin AlP (l6.4±5.6 %) were significantly higher than those in control patients (7.5±2.7 %). However, the ratios of CD4 positive cells producing IL-4 were not different between AlP and controls. The levels of IFN-')'by the stimulated lymphocytes of AlP (196 ±56 pg/ml) were significantly higher than those in the controls ( 35 ± 23 pg/ml) . However, IL-4 secretion in both groups were below detectable levels (10 pg/ml). Conclusion: An autoimmune mechanism against CA-II or LF, and Thl-type of the immune response may be involved in AlP. 2182 INCREASED SERUM LEVELS OF FOOD ANTIGEN-SPECIFIC IMMUNOGLOBULIN E IN PATIENTS WITH CHRONIC PANCREA TITIS (CP). Martin Raithel, Harald Dormann, Dieter Schwab, Sandra Winterkamp, Michael Weidenhiller, Eckhart Georg Hahn, Thomas Schneider, Dept of Medicine I, Univ of Erlangen, Erlangen, Germany. Background:Despite avoidance of food with high fat content, some patients with CP report on further abdominal symptoms (bloating, diarrhea, pain) after ingestion of certain meals. Methods:To address this question of food allergy in CP, blood samples from 14 non-atopic patients with CP or 10 controls (bleeding from angiodysplasia, choledocholithiasis) were drawn for immunoglobulin E (lgE) detection. Total and allergen-specific serum IgE (RAST; milk, egg, soy, pork, beef, fish, shrimp, fluor, hazelnut; U/ml) were detected by immunofluorescence (Pharmacia Unicap). Results:Nonatopic patients with CP were found to contain significantly higher total serum IgE levels (647±;p=0.001) than controls (62.9±). Moreover, the frequency of food-specific IgE antibodies was clearly higher in CP (61 14patients; 42.8%) than in controls (1/10; 10%). Among CP patients with detectable allergen-specific IgE the most often determined IgE antibodiese were directed to milk (50%), shrimp (50%), pork (33%), soy (16%) and hazelnut (16%). Conclusion:This study demonstrates that CP is a condition which favours increased IgE production. The increased IgE production may result from diminished efficiacy of pancreatic food digestion, inducing an increased intestinal antigen uptake which might stimulate IgE production. Allergen-specific IgE is mostly directed towards commonly used foodstuffs (milk, shrimp etc) and is present in approximately 42% of patients with CPo The increased presence of allergen-specific IgE antibodies might thus explain some type of adverse reactions to certain foodstuffs in pancreatitis patients. Food-specific IgE detection might thus provide a new approach to further clarify abdominal discomfort in patients with CP. 2183 LONG-TIME OUTCOME AND QUALITY OF LIFE AFTER ENDOSCOPIC THERAPY OF PERIPANCREATIC CYSTIC LESIONS. Hans Seifert, Sabine Bohnacker, Knut Kehlbeck, Nib Soehendra, Clin der J W Goethe-Universitaet, Med Clin II, Frankfurt, Germany; Univ Hosp Eppendorf, Hamburg, Germany; Dept of Interdisciplinary Endoscopy, Univ Hosp, Hamburg, Germany. Background: Since 1985, endoscopic therapy of pancreatic pseudocysts has developed from transpapillary drainage into transmural drainage also of infected lesions. Interventional endosonography ras widened its applications and reduced the risks. While technical feasibility and success rates have been documented, long time outcome studies are lacking. Study aims: Monitoring of long-time results regarding objective and subjective criteria as well as prospective follow-up (FU) of the pancreas-related quality of life (pLQ) in all patients treated from 1985-1995. Methods: A. Documentation of patient characteristics, indications for therapy, endoscopic techniques and success rates. B. Developing and validating a suitable pLQ-questionnaire. C. Determination of pLQ in 1995 and 1999. Results: A. 104 pts treated, 73 male, median age 49yrs (17-87, range), indications for tretment (%): pain (79), nausea or vomiting (71), cyst growth or persistence (28), weight loss (21), infection (14), bile duct obstruction (10). Endoscopic access was (n): transpapillary only (33), transmural (64), with nasocystic tube (32); technical success rate was 1001104. Complications (n): infection (15), bleeding (6, 3 operated), puncture of gall bladder (1), pneumoperitonum (I). Procedure-related and 30-day mortality were 0, hospital mortality was 2. 15 pts died during the FU-period, 20 were operated. B. A pQL-questionnaire was developed comprising II scales regarding gastrointestinal function, pain, pancreatic function. It was validated in terms of internal consistency, validity, stability. C. FU was successful in 73 pts, lost to FU were 17. Median FU was 6.5 yrs (0.9-13.7). pLQ-scores (range: 0, optimal 100, worst) were good (0-25) in 72% (corresponding e.g. with pain-score 0 in 49%), poor in 12%. Surgery did not improve outcome in 4/5
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pts with highest scores. Scores were not significantly different comparing 1995 and 1999. Conclusion: Long-time outcome ofpLQ was favourable in <70% of pts and remained stable over 5 yrs. 2184 OUTCOME OF ENDOSCOPIC PANCREATIC PLASTIC STENT· ING FOR SYMPTOMATIC PATIENTS WITH A UNIQUE MAIN PANCREATIC DUCT STENOSIS ON ALCOHOLIC CALCIFIED CHRONIC PANCREATITIS (TYPE IV CREMER). RESULTS ON 22 CONSECUTIVE PATIENTS. IS IT A PRIVILEGED INDICATION? Jean-Marc Simler, Patrick Hastier, Laurent Zermati, Rmi Dumas, Patrick Rampal, Archet II Univ Hosp, Nice, France. Aim: Evaluate on two criteria, pain and weight, the efficacy of endoscopic stenting among patients with a symptomatic unique main pancreatic duct stenosis on alcoholic chronic pancreatitis. Patients and Methods: Twentytwo consecutive patients; mean age 50 years (34-76), underwent endoscopic stenting from October 1992 to March 1999. Results: Three patients had isolated pancreatic sphincterotomy (PS), 19 had PS and insertion of a plastic stent, two patients needed two sessions of extracorporeal-shock wave lithotripsy (ESWL). Mean duration for stent drainage was 9.18 months (3-21). The mean number of stents was 3.41 (1-11). Pancreatic stents were well tolerated in 100 % cases. Mean time for follow-up after stent removal was 24.86 months (7-62). Nineteen patients on 22 were asymptomatic since the removal of the stents. Two patients needed minor pain relievers. One patients was treated with surgical pancreatico-jejunal anastomosis after the failure of endoscopic management. Main pancreatic duct clearance was achieved on 21 out of 22 patients. Pain relief was followed by a mean weight gain of 3.9 kg (1-10). Eight patients out of 22 had diabetes before entering the endoscopic program ; their endocrine function was not improved as an outcome. Conclusion: Our study shows the dramatic influence of endoscopic management in a specific sub-group of patients with a unique main pancreatic duct stenosis on chronic calcified pancreatitis (type IV Cremer). Such results should emphasize the need for a larger controlled study with endoscopic stenting versus surgical management. 2185 ETIOLOGICAL RISK FACTORS FOR FAMILIAL PANCREATITIS. P. Simon, K. P. Zimmer, W. Domschke, M. M. Lerch, Dept of Medicine B, Muenster Univ, Muenster, Germany; Dept of Pediatric, Muenster Univ, Muenster, Germany. An estimated 10% of patients with diseases of the pancreas present with a family history that indicates a genetic predisposition. We have tried to identify the underlying etiological risk factors for the onset of pancreatitis in these patients. Methods: A total of 135 outpatients were referred to our tertiary referral center because of recurrent acute pancreatitis or chronic pancreatitis between August of 1998 and July of 1999 (age 6 to 79, 82 male, 53 female). Patients with one or more direct relatives who also suffered from pancreatitis were defined as having familial pancreatitis and were recruited for etiological differentiation. The referral diagnosis was confirmed by laboratory studies for pancreatic exocrine and endocrine insufficiency, CT, MRI and/or ERCP. Common and rare etiologies including endocrine, metabolic and anatomical risk factors for pancreatitis were identified by laboratory and imaging studies as well as standardized interviews of the patient and his/her extended family. Genetic risk factors were identified by mutational analysis of the cystic fibrosis conductance regulator (CFTR) and the cationic trypsinogen (PRSS-l) gene. Results: 19 of the 135 patients (14%) had one or more first degree relatives with pancreatitis. 10 of these patients (53%) carried a mutation in the cationic trypsinogen gene (exclusively RI22H). Two patients had a strong family history of alcoholism, one patient had a confirmed family history of gallstone disease and in one patient familial hyperlipidemia was found. In 5 families no etiological factor could be identified and in none of the patients and families a CFTR mutation was detected. Discussion: At our tertiary referral center the prevalence of familial pancreatitis among patients with recurrent or chronic pancreatitis was higher than expected. In 21% of these cases common and well established risk factors of pancreatitis accounted for the familial predisposition whereas CFTR mutations were not associated with familial pancreatitis. Although known mutations in the cationic trypsinogen gene represented by far the most frequent risk factor (58%) the high prevalence of patients with familial pancreatitis in which no etiological association could be identified (26%) suggests that additional - as yet unknown - disease relevant mutations or genetic factors must exist.
lymphocytes were examined by flow cytometry and ELISA. Results: More than one autoantibody was observed in all 20 patients. Serum antinuclear antibody was detected in 15 of 20 patients, anti-LF antibody in 15, anti-CA-II antibody in 12, rheumatoid factor in 7, anti-smooth muscle antibody in 5, but anti-mitochondrial antibody in none. The serum levels of anti-CA-II and LF antibody were not correlated. The ratios of HLADR+CD3+ (30.2±10.7 %), HLA-DR+CD4+ (17.0±4.5 %) and HLADR +CD8+ (25.6±4.8 %) PBLs in AlP (n= 13) were significantly higher than those in control patients (HLA-DR+CD3+, 15.3±3.0 %; HLADR+CD4+, 8.5±1.5 %; HLA-DR+CD8+, 1O.2±3.6 %). CD4+CD45RO+ (33.2±3.3 %) and CD8+CD45RO+ memory cells (22.2±4.9 %) in AlP tended to be increased compared with those in control pancreatitis patients (CD4+CD45RO+, 24.4±3.7 %; CD8 + CD45RO + , 15.8±2.7 %). A flow cytometric analysis of intracellular cytokines showed that the ratios of CD4 positive cells producing IFN-yin AlP (l6.4±5.6 %) were significantly higher than those in control patients (7.5±2.7 %). However, the ratios of CD4 positive cells producing IL-4 were not different between AlP and controls. The levels of IFN-')'by the stimulated lymphocytes of AlP (196 ±56 pg/ml) were significantly higher than those in the controls ( 35 ± 23 pg/ml) . However, IL-4 secretion in both groups were below detectable levels (10 pg/ml). Conclusion: An autoimmune mechanism against CA-II or LF, and Thl-type of the immune response may be involved in AlP. 2182 INCREASED SERUM LEVELS OF FOOD ANTIGEN-SPECIFIC IMMUNOGLOBULIN E IN PATIENTS WITH CHRONIC PANCREA TITIS (CP). Martin Raithel, Harald Dormann, Dieter Schwab, Sandra Winterkamp, Michael Weidenhiller, Eckhart Georg Hahn, Thomas Schneider, Dept of Medicine I, Univ of Erlangen, Erlangen, Germany. Background:Despite avoidance of food with high fat content, some patients with CP report on further abdominal symptoms (bloating, diarrhea, pain) after ingestion of certain meals. Methods:To address this question of food allergy in CP, blood samples from 14 non-atopic patients with CP or 10 controls (bleeding from angiodysplasia, choledocholithiasis) were drawn for immunoglobulin E (lgE) detection. Total and allergen-specific serum IgE (RAST; milk, egg, soy, pork, beef, fish, shrimp, fluor, hazelnut; U/ml) were detected by immunofluorescence (Pharmacia Unicap). Results:Nonatopic patients with CP were found to contain significantly higher total serum IgE levels (647±;p=0.001) than controls (62.9±). Moreover, the frequency of food-specific IgE antibodies was clearly higher in CP (61 14patients; 42.8%) than in controls (1/10; 10%). Among CP patients with detectable allergen-specific IgE the most often determined IgE antibodiese were directed to milk (50%), shrimp (50%), pork (33%), soy (16%) and hazelnut (16%). Conclusion:This study demonstrates that CP is a condition which favours increased IgE production. The increased IgE production may result from diminished efficiacy of pancreatic food digestion, inducing an increased intestinal antigen uptake which might stimulate IgE production. Allergen-specific IgE is mostly directed towards commonly used foodstuffs (milk, shrimp etc) and is present in approximately 42% of patients with CPo The increased presence of allergen-specific IgE antibodies might thus explain some type of adverse reactions to certain foodstuffs in pancreatitis patients. Food-specific IgE detection might thus provide a new approach to further clarify abdominal discomfort in patients with CP. 2183 LONG-TIME OUTCOME AND QUALITY OF LIFE AFTER ENDOSCOPIC THERAPY OF PERIPANCREATIC CYSTIC LESIONS. Hans Seifert, Sabine Bohnacker, Knut Kehlbeck, Nib Soehendra, Clin der J W Goethe-Universitaet, Med Clin II, Frankfurt, Germany; Univ Hosp Eppendorf, Hamburg, Germany; Dept of Interdisciplinary Endoscopy, Univ Hosp, Hamburg, Germany. Background: Since 1985, endoscopic therapy of pancreatic pseudocysts has developed from transpapillary drainage into transmural drainage also of infected lesions. Interventional endosonography ras widened its applications and reduced the risks. While technical feasibility and success rates have been documented, long time outcome studies are lacking. Study aims: Monitoring of long-time results regarding objective and subjective criteria as well as prospective follow-up (FU) of the pancreas-related quality of life (pLQ) in all patients treated from 1985-1995. Methods: A. Documentation of patient characteristics, indications for therapy, endoscopic techniques and success rates. B. Developing and validating a suitable pLQ-questionnaire. C. Determination of pLQ in 1995 and 1999. Results: A. 104 pts treated, 73 male, median age 49yrs (17-87, range), indications for tretment (%): pain (79), nausea or vomiting (71), cyst growth or persistence (28), weight loss (21), infection (14), bile duct obstruction (10). Endoscopic access was (n): transpapillary only (33), transmural (64), with nasocystic tube (32); technical success rate was 1001104. Complications (n): infection (15), bleeding (6, 3 operated), puncture of gall bladder (1), pneumoperitonum (I). Procedure-related and 30-day mortality were 0, hospital mortality was 2. 15 pts died during the FU-period, 20 were operated. B. A pQL-questionnaire was developed comprising II scales regarding gastrointestinal function, pain, pancreatic function. It was validated in terms of internal consistency, validity, stability. C. FU was successful in 73 pts, lost to FU were 17. Median FU was 6.5 yrs (0.9-13.7). pLQ-scores (range: 0, optimal 100, worst) were good (0-25) in 72% (corresponding e.g. with pain-score 0 in 49%), poor in 12%. Surgery did not improve outcome in 4/5
AGAA423
pts with highest scores. Scores were not significantly different comparing 1995 and 1999. Conclusion: Long-time outcome ofpLQ was favourable in <70% of pts and remained stable over 5 yrs. 2184 OUTCOME OF ENDOSCOPIC PANCREATIC PLASTIC STENT· ING FOR SYMPTOMATIC PATIENTS WITH A UNIQUE MAIN PANCREATIC DUCT STENOSIS ON ALCOHOLIC CALCIFIED CHRONIC PANCREATITIS (TYPE IV CREMER). RESULTS ON 22 CONSECUTIVE PATIENTS. IS IT A PRIVILEGED INDICATION? Jean-Marc Simler, Patrick Hastier, Laurent Zermati, Rmi Dumas, Patrick Rampal, Archet II Univ Hosp, Nice, France. Aim: Evaluate on two criteria, pain and weight, the efficacy of endoscopic stenting among patients with a symptomatic unique main pancreatic duct stenosis on alcoholic chronic pancreatitis. Patients and Methods: Twentytwo consecutive patients; mean age 50 years (34-76), underwent endoscopic stenting from October 1992 to March 1999. Results: Three patients had isolated pancreatic sphincterotomy (PS), 19 had PS and insertion of a plastic stent, two patients needed two sessions of extracorporeal-shock wave lithotripsy (ESWL). Mean duration for stent drainage was 9.18 months (3-21). The mean number of stents was 3.41 (1-11). Pancreatic stents were well tolerated in 100 % cases. Mean time for follow-up after stent removal was 24.86 months (7-62). Nineteen patients on 22 were asymptomatic since the removal of the stents. Two patients needed minor pain relievers. One patients was treated with surgical pancreatico-jejunal anastomosis after the failure of endoscopic management. Main pancreatic duct clearance was achieved on 21 out of 22 patients. Pain relief was followed by a mean weight gain of 3.9 kg (1-10). Eight patients out of 22 had diabetes before entering the endoscopic program ; their endocrine function was not improved as an outcome. Conclusion: Our study shows the dramatic influence of endoscopic management in a specific sub-group of patients with a unique main pancreatic duct stenosis on chronic calcified pancreatitis (type IV Cremer). Such results should emphasize the need for a larger controlled study with endoscopic stenting versus surgical management. 2185 ETIOLOGICAL RISK FACTORS FOR FAMILIAL PANCREATITIS. P. Simon, K. P. Zimmer, W. Domschke, M. M. Lerch, Dept of Medicine B, Muenster Univ, Muenster, Germany; Dept of Pediatric, Muenster Univ, Muenster, Germany. An estimated 10% of patients with diseases of the pancreas present with a family history that indicates a genetic predisposition. We have tried to identify the underlying etiological risk factors for the onset of pancreatitis in these patients. Methods: A total of 135 outpatients were referred to our tertiary referral center because of recurrent acute pancreatitis or chronic pancreatitis between August of 1998 and July of 1999 (age 6 to 79, 82 male, 53 female). Patients with one or more direct relatives who also suffered from pancreatitis were defined as having familial pancreatitis and were recruited for etiological differentiation. The referral diagnosis was confirmed by laboratory studies for pancreatic exocrine and endocrine insufficiency, CT, MRI and/or ERCP. Common and rare etiologies including endocrine, metabolic and anatomical risk factors for pancreatitis were identified by laboratory and imaging studies as well as standardized interviews of the patient and his/her extended family. Genetic risk factors were identified by mutational analysis of the cystic fibrosis conductance regulator (CFTR) and the cationic trypsinogen (PRSS-l) gene. Results: 19 of the 135 patients (14%) had one or more first degree relatives with pancreatitis. 10 of these patients (53%) carried a mutation in the cationic trypsinogen gene (exclusively RI22H). Two patients had a strong family history of alcoholism, one patient had a confirmed family history of gallstone disease and in one patient familial hyperlipidemia was found. In 5 families no etiological factor could be identified and in none of the patients and families a CFTR mutation was detected. Discussion: At our tertiary referral center the prevalence of familial pancreatitis among patients with recurrent or chronic pancreatitis was higher than expected. In 21% of these cases common and well established risk factors of pancreatitis accounted for the familial predisposition whereas CFTR mutations were not associated with familial pancreatitis. Although known mutations in the cationic trypsinogen gene represented by far the most frequent risk factor (58%) the high prevalence of patients with familial pancreatitis in which no etiological association could be identified (26%) suggests that additional - as yet unknown - disease relevant mutations or genetic factors must exist.