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The Long Term Clinical Outcome of Patients Without Low Dose Steroid Maintenance Treatment for Autoimmune Pancreatitis
Patients followed longitudinally at our pancreas center for chronic pancreatitis since 2004 were retrospectively identified using ICD-9 and procedural codes. Charts were abstracted for demographic, procedural and hospitalization data. Pain type was defined by patient reports and clinical notes. Per the Ammann criteria, patients were classified into three pain categories; type A (intermittent acute), type B (continuous) or combination pain. ANOVA and chi square tests were used to perform univariate analysis, which were then followed by multivariate analysis controlling for significant associations. The study was approved by the Committee for the Protection of Human Subjects. RESULTS: 434 patients were seen at our center for evaluation of chronic pancreatitis between 2004 and November 2010. 294 patients who did not have complete outpatient records, were not having pain, or did not have adequate pain assessments were excluded, leaving 140 patients for analysis. The groups were similar in regards to age, years since diagnosis, pack years smoking, number of alcoholic drinks per day, and the presence of pancreatic exocrine insufficiency. However, compared to patients with type A and B pain, patients with combined pain were more likely to be male (59% vs. 48% vs. 49%, p=0.02) and obese (BMI 30 vs. 25 vs. 25, p<0.01). Patients with type A pain were more likely to have a genetic etiology (16% vs. 4% vs. 1%, p<0.01) and be diabetic (55% vs. 24% vs. 8%, p=0.01) than patients with type B or combined pain respectively. Multivariate analysis revealed an Odds Ratio of 1.7 (95% CI 1.2-2.7) for patients with obesity to have combined pain and 3.1 for patients with a genetic etiology to their pancreatitis to have type A pain (95% CI 2.4-3.8). CONCLUSIONS: Obesity and a genetic etiology appear to be associated with specific pain patterns in chronic pancreatitis. Su2069 Long-Term Pain Relief With Optimized Medical Therapy Including Antioxidants in Patients With Chronic Pancreatitis S. Shalimar, Shallu Midha, Payal Bhardwaj, Pramod K. Garg
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Background: Pain due to chronic pancreatitis (CP) is difficult to treat. We and others have shown that antioxidants relieve pain of chronic pancreatitis at least in the short-term. Objective: To study the long-term results of optimized medical therapy including antioxidants for pain relief in patients with CP. Methods: All consecutive patients with CP were included in the study prospectively after an informed consent and ethical clearance. They were treated medically with a well-balanced diet, pancreatic enzymes, and antioxidants (9000 IU betacarotene, 0.54 g vitamin C, 270 IU vitamin E, 600 ug organic selenium, and 2 g methionine; given for 6 months to one year). Endoscopic therapy and/or surgery were offered if medical therapy failed. The response to therapy was evaluated with a composite pain score and the need for hospitalization. Pain relief was the primary outcome measure. Results: A total of 226 patients (178 males) with CP were included. The etiology was idiopathic in 167 (73.9%), alcohol in 53 (23.5%) and miscellaneous in 6 (2.6%) patients. The mean age at onset of CP was 22.31 years for idiopathic and 36.86 years for alcohol related CP. The mean followup of patients was 8.71±6.42 years. 208 (92%) patients had abdominal pain. At one year follow up, significant pain relief was achieved in 81.7% of patients: 45.6% with medical therapy, 11.1% spontaneously, 18.3% with endotherapy and 6.7% with surgery. The mean pain score decreased from 6.33±1.94 to 3.09±3.34 (p<0.001). Of 208 patients, 193, 151, and 80 patients were followed up for 3, 5 and 10 years respectively; 53.4%, 58.3% and 67.5% of them became pain free at those follow-up periods respectively. Diabetes and steatorrhea developed in 35.4% and 11.1% of patients respectively. Portal vein thrombosis, biliary stricture and pseudocyst were seen in 4%, 8.8% and 21.7% of patients respectively. Pancreatic cancer developed in 4 (1.7%) patients. Conclusion: Optimized medical therapy including antioxidants resulted in long lasting pain relief in over 50% of patients with CP and in 80% of patients with additional intervention(s).
Practice of Pancreatic Enzyme Replacement Therapy in Patients With Exocrine Insufficiency; A North European Survey Edmée C. Sikkens, Djuna L. Cahen, Casper H. van Eijck, Ernst J. Kuipers, Marco J. Bruno Introduction: Treating exocrine pancreatic insufficiency (EPI) consists of pancreatic enzyme replacement according to dietary fat intake. Prescribing and using a sufficient dose of enzymes is mandatory for the treatment to be effective and ameliorate steatorrhea related symptoms. At present, it is unknown whether EPI patients receive proper treatment. In this study the practice of EPI treatment was evaluated in two north European countries. Methods: An anonymous survey was distributed to the members of the Dutch and German Associations of Patients with Pancreatic Disorders. All patients using pancreatic enzymes (PE) for EPI were included. The questionnaire focused on enzyme usage, referral to a dietician, dietary restrictions, and steatorrhea-related symptoms (bloating, abdominal cramps, bulky and foul smelling stools). Results: 405 members returned the questionnaire, of which 182 (45%) met the inclusion criteria. The mean age of the population was 58 yrs and 47% was male. EPI was caused by chronic pancreatitis (CP) in 137 patients (75%) and was due to a malignancy in 45 patients (25%). Ninety-one (50%) patients underwent surgery (resection procedures in 84% and a pancreaticojejunostomy in 16%). The most important outcomes of this survey are summarized in Table 1. The overall median PE intake was only 5 capsules per day, with 25% of patients taking 3 or less capsules per day. The majority of the patients reported symptoms of steatorrhea, which means that these patients were under-dosed. Only 30% of the patients were referred to a dietician and 65% maintained unnecessary self-imposed or dietician-instructed dietary restrictions. There were no apparent differences of enzyme treatment between patients with CP and a malignancy or operated and non-operated patients. Conclusions: EPI treatment is sub-optimal in all subgroups of patients, in countries with well-organized health care systems. In order to improve treatment efficacy, physicians and/ or dietitians should increase the dosage of PE guided by steatorrhea related symptoms and dietary fat intake. Furthermore, EPI patients should be referred to a dietitian on a standard basis. Table 1; Outcomes
Su2070 The Long Term Clinical Outcome of Patients Without Low Dose Steroid Maintenance Treatment for Autoimmune Pancreatitis Jaihwan Kim, Yong-Tae Kim, Dong-Won Ahn, Won Jae Yoon, Ji Kon Ryu, Yong Bum Yoon Background: Though maintenance steroid treatment is recommended for autoimmune pancreatitis (AIP), clinical evidence is limited. Long term use of steroid can cause many complications. The aim of this study was to see the long term outcomes of patients who did not receive maintenance treatment for AIP. Method: Nineteen AIP patients received induction steroid treatment without maintenance therapy. Their medical records were analyzed retrospectively. The criteria of pancreatic relapse were defined as symptom occurrence such as abdominal pain or jaundice with or without radiologic or serologic evidence. Result: Male patients were 14 (73.7%) and the median age was 62 (16-81) years. Other organ involvement was noticed in 12 (63.2%). The initial dose of prednisolone was from 30 to 60 mg and the median duration of induction treatment was 56 (21-155) days. The median follow-up duration was 34.5 (8.6-109.9) months. Pancreatic relapse was found in 5 (26.3%) and extrapancreatic relapse in 3 (15.8%). The median time to pancreatic relapse was 11.4 (8.022.8) months. However there was no pancreatic relapse after 22.8 months. The number of episode of pancreatic relapse was once in 3 patients and three times in 2. Two of the once relapsed cases in the pancreas were successfully treated with short term steroid administration and one was recovered without steroid treatment. One patient who had experienced recurrent relapse needed maintenance steroid therapy but underwent hepaticojejunostomy due to persisting jaundice, and the other recovered with intermittent short term steroid therapy. Three patients with extrapancreatic involvement needed maintenance therapy. Conclusion: The most of AIP patients can be treated successfully with induction or intermittent steroid administration without maintenance therapy. Maintenance therapy is needed in a small proportion of patients usually because of extrapancreatic manifestations.
* HL capsules consisting of 25.000 FIP-E units of lipase Su2068 Clinical Predictors of Pain Patterns in Chronic Pancreatitis Clark Judge, Stuart R. Gordon, Timothy B. Gardner Background & Aims: Pain from chronic pancreatitis is classified as type A (intermittent acute), type B (continuous) or combined types A and B. We sought to identify which clinical and patient characteristics are predictive of pain type in chronic pancreatitis. Methods:
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database was queried for AIP or CP with severe chronic inflammation and significant fibrosis. Paraffin-embedded specimens were stained for IgG4 and reviewed by two GI pathologists. AIP was confirmed based on the presence of lymphoplasmocytic infiltrate, obliterative phlebitis, with or without positive IgG4 staining (≥10 IgG4+ plasma cells/hpf). Patients who were treated with corticosteroids were excluded. The medical records were reviewed for clinical and follow-up information. The national death index was queried for mortality. Results: We identified 17 patients with AIP who have been evaluated at our institute from 1997 to 2010. All patients had their AIP confirmed by histologic examination of pancreatic tissue obtained by Whipple procedure (n=5), distal pancreatectomy (n=6), or biopsy (n= 6). 4 cases were from 2006 to 2010 and the remaining cases from 1997 to 2005. Of note, only 6 cases had an initial histologic diagnosis of AIP and all of them were from 2005 or later. The median age at presentation was 55 years (range: 18-78) and 58.8% were men. None of these patients received corticosteroid treatment. The patients who had surgical resection have been followed up for a median 39 months [range 1-165 months; mean 48.1 (±49.2)]. In this group, 1 patient developed CP, 3 developed biliary involvement, 1 acute recurrent pancreatitis, and 3 developed AIP-related autoimmune diseases [ulcerative colitis (1); hypothyroidism (2)] during the follow-up period. One patient died at 110 months after the initial diagnosis. The patients who had biopsy have been followed up for a median 42 months [range (1-122); mean 54.3 (±51.0)], one had persistent biliary involvement and one developed exocrine deficiency 7 years after the diagnosis. None of these patients developed pancreatic cancer during follow-up. The Kaplan-Meier survival curve is shown in figure 1. Conclusions: Our results highlight the persistence and progressive nature of AIP during its natural course and suggest AIP is not associated with high risk of pancreatic adenocarcinoma. Clinical implication: histologic material of “usual” chronic pancreatitis should be reviewed retrospectively by GI pathologists if the disease is persistent and progressive for an optimal clinical management of patients with AIP.
AGA Abstracts
which could affect IE (2); thus, 19 patients constituted the study cohort including 15 with idiopathic CP. The median CP duration was 4 years (2-20). Eight pts had CP ≥ 5 years, and the median IE was 670,083 islets (433,380 to 1,181,137). Eleven 11 pts had CP for less than 5 years and the median IE was 537,133 (37,248-792,033), and differences were not significant (p >0.05). This result was linear, so it remained insignificant when more or less years of CP duration were considered. A subset analysis of patients with idiopathic CP only (n=15) showed that patients with a duration of CP ≥ 10 yrs (n=4) had a significantly lower IE (446,354 islets) compared to pts with CP duration < 10 yrs (595,333 islets), p= 0.01. This difference did not exist when a cut-off of 5 yrs was used. Conclusion. Overall, the islet yield did not vary according to duration of CP in our cohort. In patients with idiopathic chronic pancreatitis the IE decreased after 10 yrs of disease duration. This indicates that TP/IAT can be considered as a therapeutic option in qualified patients with CP regardless of disease duration. In pts with idiopathic CP islet yield was better before 10 yrs of disease duration thus TP/IAT should be discussed earlier in this pt population. Su2073 Endoplasmic Reticulum Stress is Persistently Present in Chronic Pancreatitis Independent of Trypsinogen Activation Raghuwansh P. Sah, Rajinder Dawra, Vikas Dudeja, Sulagna Banerjee, Nameeta Mujumdar, Ashley Bekolay, Ashok Saluja BACKGROUND AND AIMS: Our understanding of the initial events during pancreatitis has centered on intra-acinar cell trypsinogen activation. Recently, endoplasmic reticulum (ER) stress has been observed early during acute pancreatitis (AP). However, the role of trypsinogen activation in inducing ER stress is currently unknown. Furthermore, hereditary pancreatitis associated mutation in Chymotrypsinogen C, which leads to increased intra-acinar trypsin, has been shown to induce ER stress in pancreatic acini in-vitro [Sahin-Toth, Gut 2010;59:365372] suggesting possible involvement of ER stress in Chronic Pancreatitis (CP). In this study, we aimed to explore ER stress in CP and establish the role of trypsinogen activation in ER stress induction in both AP and CP. METHODS: AP was induced by caerulein (50μg/kg i.p.) given every hour upto 10 hours. CP was induced by caerulein (50μg/kg i.p. every hour X 6) twice a week for 10 weeks. The levels of GRP 78 (an ER stress related molecular chaperone), cleavage of ER stress sensor ATF-6, phosphorylation of PERK (another ER stress sensor) and eIF2α and induction of transcription factor ATF4 and downstream mediator CHOP which mediates cell death, were studied by Western Blot (WB) and Immunohistochemistry (IHC). We compared ER stress during AP and CP in the presence and absence of trypsinogen activation. Novel knockout mice (T-/-) lacking trypsinogen 7 gene (the mouse correlate of human cationic trypsinogen) and cathepsin B knockout mice (CB-/-) were used for these studies. Both T-/- and CB-/- mice lack significant pathologic trypsinogen activation. RESULTS: ER stress was observed as early as 30 minutes during AP but resolved by 24 hours in our model. However, in CP, persistent elevation in GRP78, cleavage of ATF6 and phosphorylation of PERK and eIF2, and persistent induction of ATF4 were seen. These markers of ER stress were localized to acinar cells in CP by IHC. Quantification by WB revealed 3 and 7 fold rise in GRP78 and CHOP respectively. Together, these data establish the presence of chronic ER stress in acinar cells in CP. When AP was induced in T-/- mice, the levels of GRP78, ATF4 and CHOP were comparable to wild type mice (2, 15 and 3 fold, respectively, vs. controls) indicating the presence of similar ER stress during AP in the presence and absence of trypsinogen activation. Further, CB-/- mice which lack intra-acinar trypsinogen activation demonstrated chronic ER stress in CP similar to the wild type mice in all of the above markers. CONCLUSIONS: Intra-acinar cell ER stress is persistently present in chronic pancreatitis. ER stress is independent of trypsinogen activation in both acute and chronic pancreatitis. Chronic ER stress, known to activate inflammatory pathways, may be one of the mechanisms independent of trypsinogen activation, responsible for the pathogenesis of chronic pancreatitis.
Pancreatic relapse according to time in autoimmune pancreatitis patients without maintenance therapy Su2071 Is Type 2 Autoimmune Pancreatitis Rare in Asia? Prevalence, Clinical Outcomes, Radiological Features and Response to Steroids of Type 2 Autoimmune Pancreatitis in Korea Tae Jun Song, Myung-Hwan Kim, Hong Jun Kim, Choong Heon Ryu, Do Hyun Park, Sang Soo Lee, Dong Wan Seo, Sung Koo Lee Backgrounds: Recently, two distinct histological patterns of autoimmune pancreatitis (AIP), type 1 AIP and type 2 AIP, have been recognized. Type 2 AIP has been reported mainly in western countries and is known to be rare in Asia. The aim of this study was to compare the prevalence, clinical profiles, radiological findings and response to steroids of type 1 and type 2 AIP in Korea. Methods: From 120 patients diagnosed with AIP between January 2003 and March 2010, 52 patients with histologically confirmed type 1 (n=37) or type 2 (n=15) AIP were included. We reviewed the prospectively collected data on these patients. Results: The type 2 AIP patients' median age (34 years) was significantly lower than that of the type 1 AIP patients (61 years) (p<0.05). At initial presentation, severe abdominal pain (13.5% in type 1 AIP vs. 60.0% in type 2 AIP, p<0.05) and presentation as acute pancreatitis (2.7% in type 1 AIP vs. 40.0% in type 2 AIP, p<0.05) were more frequent in type 2 AIP patients than in type 1 AIP patients. Jaundice, however, was more frequent in type 1 (67.6%) than type 2 (33.3%) AIP patients (p<0.05). The pancreatic enlargement on CT scan and the main pancreatic duct stricture on endoscopic retrograde pancreatography did not differ significantly between the two groups, but a capsule-like rim was more frequent in type 1 AIP patients (48.6% vs.6.7%, p<0.05). All type 2 AIP patients showed normal serum immunoglobulin (Ig) G and IgG4 levels (IgG >1,800 mg/dL, 54.1% in type 1 AIP vs. 0% in type 2, p<0.05; IgG4 >135 mg/dL, 70.3% in type 1 AIP vs. 0% in type 2 AIP, p<0.05). Ulcerative colitis was associated with only type 2 AIP (33.3%), but type 2 AIP patients had no other extrapancreatic involvements. Steroid therapy was performed on 41 patients (27 in type 1 AIP and 14 in type 2 AIP), and all of whom improved clinically and radiologically in response to it. During the follow-up period (median 714 days in type 1 AIP vs. 489 days in type 2 AIP, p=0.166), 32.4% of type 1 AIP patients experienced a relapse, but none of the type 2 AIP patients did (p<0.05). Conclusion: It is suggested that type 2 AIP might not be rare in Korea unlike the results of previous studies. Type 1 and type 2 AIP patients had similar radiological findings and response to steroids, but they showed distinct initial clinical presentations, serology and relapse rate.
Su2074 Blockade of Nerve Growth Factor (NGF) Reverses Hyperalgesia and Nociceptor Excitability in Chronic Pancreatitis Yaohui Zhu, Mohan M. Shenoy, Liansheng Liu, Kshama R. Mehta, Tugba Colak, Pankaj J. Pasricha INTRODUCTION: Although pain is a cardinal feature of chronic pancreatitis (CP), its pathogenesis is poorly understood and treatment remains difficult. Nociceptive sensitization in several somatic pain models has been associated with nerve growth factor (NGF) and anti-NGF treatment has been shown to be effective in both experimental and clinical studies of somatic pain. We have previously shown that NGF is upregulated in a rat model of CP with accompanying hyperalgesia, nociceptor excitability and changes in both potassium (IA) and TRPV1 currents. In this study we hypothesized that neutralization of NGF would reverse these changes. METHODS: CP was induced by intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats, as previously described. In a separate group of rats, the pancreas was injected with DiI to retrogradely label sensory neurons in dorsal root ganglia (DRG) followed by intraductal TNBS. After 3 weeks, anti-NGF antibody or control serum (16ug/ kg BW) were injected intra peritoneally daily for 1 week. Pancreatic hyperalgesia was assessed by nocifensive behavior to electrical stimulation of the pancreas as well as by referred somatic pain assessed by von Frey filament (VFF). Pancreas-specific nociceptors that express TRPV1 were also assessed by immnostaining. TRPV1 and potassium currents were analyzed by patch-clamp in pancreas-specific DRG neurons labeled by DiI. RESULTS: Blockade of NGF significantly attenuated pancreatic hyperalgesia and referred somatic pain compared to control serum treated group (Figure 1). Anti-NGF had no effect on control (healthy) rats. Neutralizing also significantly decreased in the percentage of TRPV1 expression i.e. 59.03±8.57 in vehicle treated rats and 43.8±3.35 in anti-NGF treated rats (P=0.02). Treatment with anti-NGF antibody stabilized neural excitability in pancreas-specific nociceptors with the resting membrane potential (mV) of -55.35±7.03 (n=12) in contrast to -48.9±7.4 in vehicle-treated rats (n=11, P<0.05) while rheobase increased to 0.45±0.2nA (n=17) versus to 0.15±0.07 in vehicle treated rats (n=27, P=0.03). TRPV1 current density (pA/pF) in anti-NGF treated rats averaged 35.4±13.57 (n=28), as compared with 54.4±8.05 in vehicle-treated rats (n=19, P<0.05). Outward currents in responding to stepwise depolarizing pulses in switching
Su2072 Does the Duration of Chronic Pancreatitis Affect the Islet Yield During Total Pancreatectomy and Islet Cell Auto-Transplantation? Luis F. Lara, Morihito Takita, Shinichi Matsumoto, Jeffrey Lamont, Goran Klintmalm, Marlon F. Levy Background/Aims Chronic pancreatitis (CP) is a progressive disease which produces significant pain and narcotic dependence. Disease management remains a challenge. Total pancreatectomy with islet autotransplantation (TP/IAT) is an effective therapy to treat incapacitating pain in highly selected patients with CP. Predicting the islet yield (IE) is important to identify suitable candidates that could achieve insulin independence. Disease severity and BMI affect the IE, but the association between duration of CP and IE is not clear. We determined if there was a correlation between duration of disease and IE. Methods. TP/IAT has been performed at our institution since 2006, and a new pancreas isolation method was established in 2007. After TP pancreata are preserved using chilled ET-Kyoto solution and preserved using the oxygen-charged static two layer method. Pancreas digestion is performed using the modified Ricordi method. Islets are purified when over 10 ml of tissue is obtained to avoid increased portal pressure and portal vein thrombosis, and injected into the portal vein over 30-60 minutes as long as portal pressure remains < 22 mmHg. IE of over 500,000 islets is considered successful, and correlates with a higher likelihood of insulin independence. Post-digestion IE were obtained and were compared to the time since diagnosis of CP to determine if IE varied with longer disease duration. Results. Twenty six patients (pts) have undergone TP/IAT since 2006. Seven pts were excluded because islets were isolated using our previous method (3), ductal injection failed (2), or pts had previous pancreas resection
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Background: Pain due to chronic pancreatitis (CP) is difficult to treat. We and others have shown that antioxidants relieve pain of chronic pancreatitis at least in the short-term. Objective: To study the long-term results of optimized medical therapy including antioxidants for pain relief in patients with CP. Methods: All consecutive patients with CP were included in the study prospectively after an informed consent and ethical clearance. They were treated medically with a well-balanced diet, pancreatic enzymes, and antioxidants (9000 IU betacarotene, 0.54 g vitamin C, 270 IU vitamin E, 600 ug organic selenium, and 2 g methionine; given for 6 months to one year). Endoscopic therapy and/or surgery were offered if medical therapy failed. The response to therapy was evaluated with a composite pain score and the need for hospitalization. Pain relief was the primary outcome measure. Results: A total of 226 patients (178 males) with CP were included. The etiology was idiopathic in 167 (73.9%), alcohol in 53 (23.5%) and miscellaneous in 6 (2.6%) patients. The mean age at onset of CP was 22.31 years for idiopathic and 36.86 years for alcohol related CP. The mean followup of patients was 8.71±6.42 years. 208 (92%) patients had abdominal pain. At one year follow up, significant pain relief was achieved in 81.7% of patients: 45.6% with medical therapy, 11.1% spontaneously, 18.3% with endotherapy and 6.7% with surgery. The mean pain score decreased from 6.33±1.94 to 3.09±3.34 (p<0.001). Of 208 patients, 193, 151, and 80 patients were followed up for 3, 5 and 10 years respectively; 53.4%, 58.3% and 67.5% of them became pain free at those follow-up periods respectively. Diabetes and steatorrhea developed in 35.4% and 11.1% of patients respectively. Portal vein thrombosis, biliary stricture and pseudocyst were seen in 4%, 8.8% and 21.7% of patients respectively. Pancreatic cancer developed in 4 (1.7%) patients. Conclusion: Optimized medical therapy including antioxidants resulted in long lasting pain relief in over 50% of patients with CP and in 80% of patients with additional intervention(s).
Practice of Pancreatic Enzyme Replacement Therapy in Patients With Exocrine Insufficiency; A North European Survey Edmée C. Sikkens, Djuna L. Cahen, Casper H. van Eijck, Ernst J. Kuipers, Marco J. Bruno Introduction: Treating exocrine pancreatic insufficiency (EPI) consists of pancreatic enzyme replacement according to dietary fat intake. Prescribing and using a sufficient dose of enzymes is mandatory for the treatment to be effective and ameliorate steatorrhea related symptoms. At present, it is unknown whether EPI patients receive proper treatment. In this study the practice of EPI treatment was evaluated in two north European countries. Methods: An anonymous survey was distributed to the members of the Dutch and German Associations of Patients with Pancreatic Disorders. All patients using pancreatic enzymes (PE) for EPI were included. The questionnaire focused on enzyme usage, referral to a dietician, dietary restrictions, and steatorrhea-related symptoms (bloating, abdominal cramps, bulky and foul smelling stools). Results: 405 members returned the questionnaire, of which 182 (45%) met the inclusion criteria. The mean age of the population was 58 yrs and 47% was male. EPI was caused by chronic pancreatitis (CP) in 137 patients (75%) and was due to a malignancy in 45 patients (25%). Ninety-one (50%) patients underwent surgery (resection procedures in 84% and a pancreaticojejunostomy in 16%). The most important outcomes of this survey are summarized in Table 1. The overall median PE intake was only 5 capsules per day, with 25% of patients taking 3 or less capsules per day. The majority of the patients reported symptoms of steatorrhea, which means that these patients were under-dosed. Only 30% of the patients were referred to a dietician and 65% maintained unnecessary self-imposed or dietician-instructed dietary restrictions. There were no apparent differences of enzyme treatment between patients with CP and a malignancy or operated and non-operated patients. Conclusions: EPI treatment is sub-optimal in all subgroups of patients, in countries with well-organized health care systems. In order to improve treatment efficacy, physicians and/ or dietitians should increase the dosage of PE guided by steatorrhea related symptoms and dietary fat intake. Furthermore, EPI patients should be referred to a dietitian on a standard basis. Table 1; Outcomes
Su2070 The Long Term Clinical Outcome of Patients Without Low Dose Steroid Maintenance Treatment for Autoimmune Pancreatitis Jaihwan Kim, Yong-Tae Kim, Dong-Won Ahn, Won Jae Yoon, Ji Kon Ryu, Yong Bum Yoon Background: Though maintenance steroid treatment is recommended for autoimmune pancreatitis (AIP), clinical evidence is limited. Long term use of steroid can cause many complications. The aim of this study was to see the long term outcomes of patients who did not receive maintenance treatment for AIP. Method: Nineteen AIP patients received induction steroid treatment without maintenance therapy. Their medical records were analyzed retrospectively. The criteria of pancreatic relapse were defined as symptom occurrence such as abdominal pain or jaundice with or without radiologic or serologic evidence. Result: Male patients were 14 (73.7%) and the median age was 62 (16-81) years. Other organ involvement was noticed in 12 (63.2%). The initial dose of prednisolone was from 30 to 60 mg and the median duration of induction treatment was 56 (21-155) days. The median follow-up duration was 34.5 (8.6-109.9) months. Pancreatic relapse was found in 5 (26.3%) and extrapancreatic relapse in 3 (15.8%). The median time to pancreatic relapse was 11.4 (8.022.8) months. However there was no pancreatic relapse after 22.8 months. The number of episode of pancreatic relapse was once in 3 patients and three times in 2. Two of the once relapsed cases in the pancreas were successfully treated with short term steroid administration and one was recovered without steroid treatment. One patient who had experienced recurrent relapse needed maintenance steroid therapy but underwent hepaticojejunostomy due to persisting jaundice, and the other recovered with intermittent short term steroid therapy. Three patients with extrapancreatic involvement needed maintenance therapy. Conclusion: The most of AIP patients can be treated successfully with induction or intermittent steroid administration without maintenance therapy. Maintenance therapy is needed in a small proportion of patients usually because of extrapancreatic manifestations.
* HL capsules consisting of 25.000 FIP-E units of lipase Su2068 Clinical Predictors of Pain Patterns in Chronic Pancreatitis Clark Judge, Stuart R. Gordon, Timothy B. Gardner Background & Aims: Pain from chronic pancreatitis is classified as type A (intermittent acute), type B (continuous) or combined types A and B. We sought to identify which clinical and patient characteristics are predictive of pain type in chronic pancreatitis. Methods:
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database was queried for AIP or CP with severe chronic inflammation and significant fibrosis. Paraffin-embedded specimens were stained for IgG4 and reviewed by two GI pathologists. AIP was confirmed based on the presence of lymphoplasmocytic infiltrate, obliterative phlebitis, with or without positive IgG4 staining (≥10 IgG4+ plasma cells/hpf). Patients who were treated with corticosteroids were excluded. The medical records were reviewed for clinical and follow-up information. The national death index was queried for mortality. Results: We identified 17 patients with AIP who have been evaluated at our institute from 1997 to 2010. All patients had their AIP confirmed by histologic examination of pancreatic tissue obtained by Whipple procedure (n=5), distal pancreatectomy (n=6), or biopsy (n= 6). 4 cases were from 2006 to 2010 and the remaining cases from 1997 to 2005. Of note, only 6 cases had an initial histologic diagnosis of AIP and all of them were from 2005 or later. The median age at presentation was 55 years (range: 18-78) and 58.8% were men. None of these patients received corticosteroid treatment. The patients who had surgical resection have been followed up for a median 39 months [range 1-165 months; mean 48.1 (±49.2)]. In this group, 1 patient developed CP, 3 developed biliary involvement, 1 acute recurrent pancreatitis, and 3 developed AIP-related autoimmune diseases [ulcerative colitis (1); hypothyroidism (2)] during the follow-up period. One patient died at 110 months after the initial diagnosis. The patients who had biopsy have been followed up for a median 42 months [range (1-122); mean 54.3 (±51.0)], one had persistent biliary involvement and one developed exocrine deficiency 7 years after the diagnosis. None of these patients developed pancreatic cancer during follow-up. The Kaplan-Meier survival curve is shown in figure 1. Conclusions: Our results highlight the persistence and progressive nature of AIP during its natural course and suggest AIP is not associated with high risk of pancreatic adenocarcinoma. Clinical implication: histologic material of “usual” chronic pancreatitis should be reviewed retrospectively by GI pathologists if the disease is persistent and progressive for an optimal clinical management of patients with AIP.
AGA Abstracts
which could affect IE (2); thus, 19 patients constituted the study cohort including 15 with idiopathic CP. The median CP duration was 4 years (2-20). Eight pts had CP ≥ 5 years, and the median IE was 670,083 islets (433,380 to 1,181,137). Eleven 11 pts had CP for less than 5 years and the median IE was 537,133 (37,248-792,033), and differences were not significant (p >0.05). This result was linear, so it remained insignificant when more or less years of CP duration were considered. A subset analysis of patients with idiopathic CP only (n=15) showed that patients with a duration of CP ≥ 10 yrs (n=4) had a significantly lower IE (446,354 islets) compared to pts with CP duration < 10 yrs (595,333 islets), p= 0.01. This difference did not exist when a cut-off of 5 yrs was used. Conclusion. Overall, the islet yield did not vary according to duration of CP in our cohort. In patients with idiopathic chronic pancreatitis the IE decreased after 10 yrs of disease duration. This indicates that TP/IAT can be considered as a therapeutic option in qualified patients with CP regardless of disease duration. In pts with idiopathic CP islet yield was better before 10 yrs of disease duration thus TP/IAT should be discussed earlier in this pt population. Su2073 Endoplasmic Reticulum Stress is Persistently Present in Chronic Pancreatitis Independent of Trypsinogen Activation Raghuwansh P. Sah, Rajinder Dawra, Vikas Dudeja, Sulagna Banerjee, Nameeta Mujumdar, Ashley Bekolay, Ashok Saluja BACKGROUND AND AIMS: Our understanding of the initial events during pancreatitis has centered on intra-acinar cell trypsinogen activation. Recently, endoplasmic reticulum (ER) stress has been observed early during acute pancreatitis (AP). However, the role of trypsinogen activation in inducing ER stress is currently unknown. Furthermore, hereditary pancreatitis associated mutation in Chymotrypsinogen C, which leads to increased intra-acinar trypsin, has been shown to induce ER stress in pancreatic acini in-vitro [Sahin-Toth, Gut 2010;59:365372] suggesting possible involvement of ER stress in Chronic Pancreatitis (CP). In this study, we aimed to explore ER stress in CP and establish the role of trypsinogen activation in ER stress induction in both AP and CP. METHODS: AP was induced by caerulein (50μg/kg i.p.) given every hour upto 10 hours. CP was induced by caerulein (50μg/kg i.p. every hour X 6) twice a week for 10 weeks. The levels of GRP 78 (an ER stress related molecular chaperone), cleavage of ER stress sensor ATF-6, phosphorylation of PERK (another ER stress sensor) and eIF2α and induction of transcription factor ATF4 and downstream mediator CHOP which mediates cell death, were studied by Western Blot (WB) and Immunohistochemistry (IHC). We compared ER stress during AP and CP in the presence and absence of trypsinogen activation. Novel knockout mice (T-/-) lacking trypsinogen 7 gene (the mouse correlate of human cationic trypsinogen) and cathepsin B knockout mice (CB-/-) were used for these studies. Both T-/- and CB-/- mice lack significant pathologic trypsinogen activation. RESULTS: ER stress was observed as early as 30 minutes during AP but resolved by 24 hours in our model. However, in CP, persistent elevation in GRP78, cleavage of ATF6 and phosphorylation of PERK and eIF2, and persistent induction of ATF4 were seen. These markers of ER stress were localized to acinar cells in CP by IHC. Quantification by WB revealed 3 and 7 fold rise in GRP78 and CHOP respectively. Together, these data establish the presence of chronic ER stress in acinar cells in CP. When AP was induced in T-/- mice, the levels of GRP78, ATF4 and CHOP were comparable to wild type mice (2, 15 and 3 fold, respectively, vs. controls) indicating the presence of similar ER stress during AP in the presence and absence of trypsinogen activation. Further, CB-/- mice which lack intra-acinar trypsinogen activation demonstrated chronic ER stress in CP similar to the wild type mice in all of the above markers. CONCLUSIONS: Intra-acinar cell ER stress is persistently present in chronic pancreatitis. ER stress is independent of trypsinogen activation in both acute and chronic pancreatitis. Chronic ER stress, known to activate inflammatory pathways, may be one of the mechanisms independent of trypsinogen activation, responsible for the pathogenesis of chronic pancreatitis.
Pancreatic relapse according to time in autoimmune pancreatitis patients without maintenance therapy Su2071 Is Type 2 Autoimmune Pancreatitis Rare in Asia? Prevalence, Clinical Outcomes, Radiological Features and Response to Steroids of Type 2 Autoimmune Pancreatitis in Korea Tae Jun Song, Myung-Hwan Kim, Hong Jun Kim, Choong Heon Ryu, Do Hyun Park, Sang Soo Lee, Dong Wan Seo, Sung Koo Lee Backgrounds: Recently, two distinct histological patterns of autoimmune pancreatitis (AIP), type 1 AIP and type 2 AIP, have been recognized. Type 2 AIP has been reported mainly in western countries and is known to be rare in Asia. The aim of this study was to compare the prevalence, clinical profiles, radiological findings and response to steroids of type 1 and type 2 AIP in Korea. Methods: From 120 patients diagnosed with AIP between January 2003 and March 2010, 52 patients with histologically confirmed type 1 (n=37) or type 2 (n=15) AIP were included. We reviewed the prospectively collected data on these patients. Results: The type 2 AIP patients' median age (34 years) was significantly lower than that of the type 1 AIP patients (61 years) (p<0.05). At initial presentation, severe abdominal pain (13.5% in type 1 AIP vs. 60.0% in type 2 AIP, p<0.05) and presentation as acute pancreatitis (2.7% in type 1 AIP vs. 40.0% in type 2 AIP, p<0.05) were more frequent in type 2 AIP patients than in type 1 AIP patients. Jaundice, however, was more frequent in type 1 (67.6%) than type 2 (33.3%) AIP patients (p<0.05). The pancreatic enlargement on CT scan and the main pancreatic duct stricture on endoscopic retrograde pancreatography did not differ significantly between the two groups, but a capsule-like rim was more frequent in type 1 AIP patients (48.6% vs.6.7%, p<0.05). All type 2 AIP patients showed normal serum immunoglobulin (Ig) G and IgG4 levels (IgG >1,800 mg/dL, 54.1% in type 1 AIP vs. 0% in type 2, p<0.05; IgG4 >135 mg/dL, 70.3% in type 1 AIP vs. 0% in type 2 AIP, p<0.05). Ulcerative colitis was associated with only type 2 AIP (33.3%), but type 2 AIP patients had no other extrapancreatic involvements. Steroid therapy was performed on 41 patients (27 in type 1 AIP and 14 in type 2 AIP), and all of whom improved clinically and radiologically in response to it. During the follow-up period (median 714 days in type 1 AIP vs. 489 days in type 2 AIP, p=0.166), 32.4% of type 1 AIP patients experienced a relapse, but none of the type 2 AIP patients did (p<0.05). Conclusion: It is suggested that type 2 AIP might not be rare in Korea unlike the results of previous studies. Type 1 and type 2 AIP patients had similar radiological findings and response to steroids, but they showed distinct initial clinical presentations, serology and relapse rate.
Su2074 Blockade of Nerve Growth Factor (NGF) Reverses Hyperalgesia and Nociceptor Excitability in Chronic Pancreatitis Yaohui Zhu, Mohan M. Shenoy, Liansheng Liu, Kshama R. Mehta, Tugba Colak, Pankaj J. Pasricha INTRODUCTION: Although pain is a cardinal feature of chronic pancreatitis (CP), its pathogenesis is poorly understood and treatment remains difficult. Nociceptive sensitization in several somatic pain models has been associated with nerve growth factor (NGF) and anti-NGF treatment has been shown to be effective in both experimental and clinical studies of somatic pain. We have previously shown that NGF is upregulated in a rat model of CP with accompanying hyperalgesia, nociceptor excitability and changes in both potassium (IA) and TRPV1 currents. In this study we hypothesized that neutralization of NGF would reverse these changes. METHODS: CP was induced by intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats, as previously described. In a separate group of rats, the pancreas was injected with DiI to retrogradely label sensory neurons in dorsal root ganglia (DRG) followed by intraductal TNBS. After 3 weeks, anti-NGF antibody or control serum (16ug/ kg BW) were injected intra peritoneally daily for 1 week. Pancreatic hyperalgesia was assessed by nocifensive behavior to electrical stimulation of the pancreas as well as by referred somatic pain assessed by von Frey filament (VFF). Pancreas-specific nociceptors that express TRPV1 were also assessed by immnostaining. TRPV1 and potassium currents were analyzed by patch-clamp in pancreas-specific DRG neurons labeled by DiI. RESULTS: Blockade of NGF significantly attenuated pancreatic hyperalgesia and referred somatic pain compared to control serum treated group (Figure 1). Anti-NGF had no effect on control (healthy) rats. Neutralizing also significantly decreased in the percentage of TRPV1 expression i.e. 59.03±8.57 in vehicle treated rats and 43.8±3.35 in anti-NGF treated rats (P=0.02). Treatment with anti-NGF antibody stabilized neural excitability in pancreas-specific nociceptors with the resting membrane potential (mV) of -55.35±7.03 (n=12) in contrast to -48.9±7.4 in vehicle-treated rats (n=11, P<0.05) while rheobase increased to 0.45±0.2nA (n=17) versus to 0.15±0.07 in vehicle treated rats (n=27, P=0.03). TRPV1 current density (pA/pF) in anti-NGF treated rats averaged 35.4±13.57 (n=28), as compared with 54.4±8.05 in vehicle-treated rats (n=19, P<0.05). Outward currents in responding to stepwise depolarizing pulses in switching
Su2072 Does the Duration of Chronic Pancreatitis Affect the Islet Yield During Total Pancreatectomy and Islet Cell Auto-Transplantation? Luis F. Lara, Morihito Takita, Shinichi Matsumoto, Jeffrey Lamont, Goran Klintmalm, Marlon F. Levy Background/Aims Chronic pancreatitis (CP) is a progressive disease which produces significant pain and narcotic dependence. Disease management remains a challenge. Total pancreatectomy with islet autotransplantation (TP/IAT) is an effective therapy to treat incapacitating pain in highly selected patients with CP. Predicting the islet yield (IE) is important to identify suitable candidates that could achieve insulin independence. Disease severity and BMI affect the IE, but the association between duration of CP and IE is not clear. We determined if there was a correlation between duration of disease and IE. Methods. TP/IAT has been performed at our institution since 2006, and a new pancreas isolation method was established in 2007. After TP pancreata are preserved using chilled ET-Kyoto solution and preserved using the oxygen-charged static two layer method. Pancreas digestion is performed using the modified Ricordi method. Islets are purified when over 10 ml of tissue is obtained to avoid increased portal pressure and portal vein thrombosis, and injected into the portal vein over 30-60 minutes as long as portal pressure remains < 22 mmHg. IE of over 500,000 islets is considered successful, and correlates with a higher likelihood of insulin independence. Post-digestion IE were obtained and were compared to the time since diagnosis of CP to determine if IE varied with longer disease duration. Results. Twenty six patients (pts) have undergone TP/IAT since 2006. Seven pts were excluded because islets were isolated using our previous method (3), ductal injection failed (2), or pts had previous pancreas resection
AGA Abstracts
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