Luca Frulloni

International Consensus Diagnostic Criteria for Autoimmune Pancreatitis: Guidelines of the International Association of Pancreatology

Objectives: To achieve the goal of developing international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP). Methods: An international panel of experts met during the 14th Congress of the International Association of Pancreatology held in Fukuoka, Japan, from July 11 through 13, 2010. The proposed criteria represent a consensus opinion of the working group. Results: Autoimmune pancreatitis was classified into types 1 and 2. The ICDC used 5 cardinal features of AIP, namely, imaging of pancreatic parenchyma and duct, serology, other organ involvement, pancreatic histology, and an optional criterion of response to steroid therapy. Each feature was categorized as level 1 and 2 findings depending on the diagnostic reliability. The diagnosis of type 1 and type 2 AIP can be definitive or probable, and in some cases, the distinction between the subtypes may not be possible (AIP-not otherwise specified). Conclusions: The ICDC for AIP were developed based on the agreement of an international panel of experts in the hope that they will promote worldwide recognition of AIP. The categorization of AIP into types 1 and 2 should be helpful for further clarification of the clinical features, pathogenesis, and natural history of these diseases.

Gabexate for the Prevention of Pancreatic Damage Related to Endoscopic Retrograde Cholangiopancreatography

BACKGROUND Endoscopic retrograde cholangiopancreatography (ERCP) is associated with elevated levels of pancreatic enzymes and pancreatitis. Gabexate, a protease inhibitor, has been used to prevent pancreatic damage related to ERCP. METHODS We conducted a multicenter, double-blind comparison of gabexate (1 g given by intravenous infusion starting 30 to 90 minutes before endoscopy and continuing for 12 hours afterward) with placebo (mannitol and sodium chloride, administered in the same fashion). A total of 435 adults scheduled to undergo ERCP and, when indicated, endoscopic sphincterotomy underwent randomization; 17 were excluded from the final analysis for various reasons. The remaining 418 patients (mean age, 60.4 years)--208 in the gabexate group and 210 in the placebo group--were analyzed. Acute pancreatitis was considered to be present if serum amylase or lipase levels (or both) were five times greater than the upper limits of normal in association with the onset of pancreatic pain. RESULTS After the procedures, 276 patients (66 percent) had elevated pancreatic-enzyme levels; the frequency was similar in the two groups. Mean serum amylase values were higher in the placebo group than in the gabexate group through 24 hours of observation (P=0.03). Twelve patients in the gabexate group and 29 in the placebo group had abdominal pain (6 percent vs. 14 percent, P=0.009). Sixteen patients in the placebo group and five in the gabexate group had acute pancreatitis (8 percent vs. 2 percent, P=0.03). Two patients treated with gabexate and six given placebo had adverse events, all of which resolved. Two patients given placebo died of acute pancreatitis; one was excluded from the evaluation because pancreatitis was present before endoscopy. One patient in the gabexate group died, from a myocardial infarction. CONCLUSION Prophylactic treatment with gabexate reduced pancreatic damage related to ERCP, as reflected by reductions in the extent but not the frequency of elevated enzyme levels and in the frequency of pancreatic pain and acute pancreatitis.

Identification of a Novel Antibody Associated with Autoimmune Pancreatitis

BACKGROUND Autoimmune pancreatitis is characterized by an inflammatory process that leads to organ dysfunction. The cause of the disease is unknown. Its autoimmune origin has been suggested but never proved, and little is known about the pathogenesis of this condition. METHODS To identify pathogenetically relevant autoantigen targets, we screened a random peptide library with pooled IgG obtained from 20 patients with autoimmune pancreatitis. Peptide-specific antibodies were detected in serum specimens obtained from the patients. RESULTS Among the detected peptides, peptide AIP(1-7) was recognized by the serum specimens from 18 of 20 patients with autoimmune pancreatitis and by serum specimens from 4 of 40 patients with pancreatic cancer, but not by serum specimens from healthy controls. The peptide showed homology with an amino acid sequence of plasminogen-binding protein (PBP) of Helicobacter pylori and with ubiquitin-protein ligase E3 component n-recognin 2 (UBR2), an enzyme highly expressed in acinar cells of the pancreas. Antibodies against the PBP peptide were detected in 19 of 20 patients with autoimmune pancreatitis (95%) and in 4 of 40 patients with pancreatic cancer (10%). Such reactivity was not detected in patients with alcohol-induced chronic pancreatitis or intraductal papillary mucinous neoplasm. The results were validated in another series of patients with autoimmune pancreatitis or pancreatic cancer: 14 of 15 patients with autoimmune pancreatitis (93%) and 1 of 70 patients with pancreatic cancer (1%) had a positive test for anti-PBP peptide antibodies. When the training and validation groups were combined, the test was positive in 33 of 35 patients with autoimmune pancreatitis (94%) and in 5 of 110 patients with pancreatic cancer (5%). CONCLUSIONS The antibody that we identified was detected in most patients with autoimmune pancreatitis but also in some patients with pancreatic cancer, making it an imperfect test to distinguish between these two conditions.

Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis

Objective Autoimmune pancreatitis (AIP) is a treatable form of chronic pancreatitis that has been increasingly recognised over the last decade. We set out to better understand the current burden of AIP at several academic institutions diagnosed using the International Consensus Diagnostic Criteria, and to describe long-term outcomes, including organs involved, treatments, relapse frequency and long-term sequelae. Design 23 institutions from 10 different countries participated in this multinational analysis. A total of 1064 patients meeting the International Consensus Diagnostic Criteria for type 1 (n=978) or type 2 (n=86) AIP were included. Data regarding treatments, relapses and sequelae were obtained. Results The majority of patients with type 1 (99%) and type 2 (92%) AIP who were treated with steroids went into clinical remission. Most patients with jaundice required biliary stent placement (71% of type 1 and 77% of type 2 AIP). Relapses were more common in patients with type 1 (31%) versus type 2 AIP (9%, p<0.001), especially those with IgG4-related sclerosing cholangitis (56% vs 26%, p<0.001). Relapses typically occurred in the pancreas or biliary tree. Retreatment with steroids remained effective at inducing remission with or without alternative treatment, such as azathioprine. Pancreatic duct stones and cancer were uncommon sequelae in type 1 AIP and did not occur in type 2 AIP during the study period. Conclusions AIP is a global disease which uniformly displays a high response to steroid treatment and tendency to relapse in the pancreas and biliary tree. Potential long-term sequelae include pancreatic duct stones and malignancy, however they were uncommon during the study period and require additional follow-up. Additional studies investigating prevention and treatment of disease relapses are needed.

International consensus guidance statement on the management and treatment of IgG4-related disease

A. Khosroshahi, Z. S. Wallace, J. L. Crowe, T. Akamizu, A. Azumi, M. N. Carruthers, S. T. Chari, E. Della-Torre, L. Frulloni, H. Goto, P. A. Hart, T. Kamisawa, S. Kawa, M. Kawano, M. H. Kim, Y. Kodama, K. Kubota, M. M. Lerch, M. L€ ohr, Y. Masaki, S. Matsui, T. Mimori, S. Nakamura, T. Nakazawa, H. Ohara, K. Okazaki, J. H. Ryu, T. Saeki, N. Schleinitz, A. Shimatsu, T. Shimosegawa, H. Takahashi, M. Takahira, A. Tanaka, M. Topazian, H. Umehara, G. J. Webster, T. E. Witzig, M. Yamamoto, W. Zhang, T. Chiba, and J. H. Stone

Alcohol and Smoking as Risk Factors in Chronic Pancreatitis and Pancreatic Cancer

The aim of this study was to compare alcohol andsmoking as risk factors in the development of chronicpancreatitis and pancreatic cancer. We considered onlymale subjects: (1) 630 patients with chronic pancreatitis who developed 12 pancreatic and 47extrapancreatic cancers; (2) 69 patients withhistologically well documented pancreatic cancer and noclinical history of chronic pancreatitis; and (3) 700 random controls taken from the Verona pollinglist and submitted to a complete medical check-up.Chronic pancreatitis subjects drink more than controlsubjects and more than subjects with pancreatic cancer without chronic pancreatitis (P < 0.001).The percentage of smokers in the group with chronicpancreatitis is significantly higher than that in thecontrol group [odds ratio (OR) 17.3; 95% CI 12.6-23.8; P < 0.001] and in the group with pancreaticcarcinomas but with no history of chronic pancreatitis(OR 5.3; 95% CI 3.0-9.4; P < 0.001). In conclusion,our study shows that: (1) the risk of chronic pancreatitis correlates both with alcoholintake and with cigarette smoking with a trendindicating that the risk increases with increasedalcohol intake and cigarette consumption; (2) alcoholand smoking are statistically independent risk factors forchronic pancreatitis; and (3) the risk of pancreaticcancer correlates positively with cigarette smoking butnot with drinking.

Autoimmune Pancreatitis: Differences Between the Focal and Diffuse Forms in 87 Patients

OBJECTIVES:Autoimmune pancreatitis (AIP) is a particular type of chronic pancreatitis that can be classified into diffuse and focal forms. The aim of this study was to analyze clinical and instrumental features of patients suffering from the diffuse and focal forms of AIP.METHODS:AIP patients diagnosed between 1995–2008 were studied.RESULTS:A total of 87 AIP patients (54 male and 33 female patients, mean age 43.4±15.3 years) were studied. Focal-type AIP was diagnosed in 63% and diffuse-type in 37%. Association with autoimmune diseases was observed in 53% of cases, the most common being ulcerative colitis (30%). Serum levels of IgG4 exceeded the upper normal limits (135 mg/dl) in 66% of focal AIP and in 27% of diffuse AIP (P=0.006). All patients responded to steroids. At recurrence non-steroid immunosuppressive drugs were successfully used in six patients. Recurrences were observed in 25% of cases, and were more frequent in focal AIP (33%) than in diffuse AIP (12%) (P=0.043), in smokers than in non-smokers (41% vs. 15%; P=0.011), and in patients with pathological serum levels of IgG4 compared to those with normal serum levels (50% vs. 12%; P=0.009). In all, 23% of the patients underwent pancreatic resections. Among patients with focal AIP, recurrences were observed in 30% of operated and in 34% of not operated patients.CONCLUSIONS:Focal-type and diffuse-type AIP differ as regards clinical symptoms and signs. Recurrences occur more frequently in focal AIP than in diffuse AIP. The use of non-steroid immunosuppressants may be a therapeutic option in relapsing AIP.

Incidence of cancer in the course of chronic pancreatitis

Objective:Chronic pancreatitis patients appear to present an increased incidence of pancreatic cancer. The aim of the study was to compare the incidence of cancer, whether pancreatic or extrapancreatic, in our chronic pancreatitis cases with that in the population of our region.Methods:We analyzed 715 cases of chronic pancreatitis with a median follow-up of 10 yr (7287 person-years); during this observation period they developed 61 neoplasms, 14 of which were pancreatic cancers. The cancer incidence rates were compared, after correction for age and gender, with those of a tumour registry.Results:We documented a significant increase in incidence of both extrapancreatic (Standardized Incidence Ratio [SIR], 1.5; 95% confidence interval [CI], 1.1–2.0; p <0.003) and pancreatic cancer (SIR, 18.5; 95% CI, 10–30; p < 0.0001) in chronic pancreatitis patients. Even when excluding from the analysis the four cases of pancreatic cancer that occurred within 4 yr of clinical onset of chronic pancreatitis, the SIR is 13.3 (95% CI, 6.4–24.5; p < 0.0001). If we exclude these early-onset cancers, there would appear to be no increased risk of pancreatic cancer in nonsmokers, whereas in smokers this risk increases 15.6-fold.Conclusions:The risks of pancreatic and nonpancreatic cancers are increased in the course of chronic pancreatitis, the former being significantly higher than the latter. The very high incidence of pancreatic cancer in smokers probably suggests that, in addition to cigarette smoking, some other factor linked to chronic inflammation of the pancreas may be responsible for the increased risk.

Clinical profile of autoimmune pancreatitis and its histological subtypes: An international multicenter survey

Objective: The objective of this study was to clarify the clinical and pathophysiological characteristics of autoimmune pancreatitis (AIP) and its subtypes (lymphoplasmacytic sclerosing pancreatitis [LPSP] and idiopathic duct-centric pancreatitis [IDCP]) seen around the world. Methods: An international multicenter survey of AIP was conducted in 15 institutes from 8 countries. We compared clinical and pathologic profiles of AIP (n = 731) and the clinical profiles of LPSP (n = 204) and IDCP (n = 64) patients. Results: Patients with LPSP were approximately 16 years older than IDCP patients. Obstructive jaundice was a more frequent presentation in LPSP versus IDCP (75% vs 47%, P < 0.001), whereas abdominal pain (41% vs 68%, P < 0.001) and acute pancreatitis (5% vs 34%, P < 0.001) were more frequent in IDCP patients. Patients with LPSP were more likely to have diffuse swelling of the pancreas (40% vs 25%, P = 0.037) and elevated serum IgG4 levels (63% vs 23%, P < 0.001) but less likely to be associated with ulcerative colitis (1% vs 16%, P < 0.001). Clinical profiles of non-histologically confirmed AIP from Asia, the United States, and United Kingdom corresponded with that of LPSP, whereas those from Italy and Germany suggested a mixture of LPSP and IDCP. Conclusions: Autoimmune pancreatitis is seen all around the world, with regional differences in the pathologic and clinical features. Lymphoplasmacytic sclerosing pancreatitis and IDCP have distinct clinical profiles.

Cigarette smoking : an independent risk factor in alcoholic pancreatitis

It is not known whether cigarette smoking plays a role as a risk factor in alcoholic pancreatitis. The aim of this study was to compare drinking and smoking habits in three groups of male subjects with an alcohol intake in excess of 40 g/day: (i) 67 patients with acute alcoholic pancreatitis, without other known potential causative agents; (ii) 396 patients with chronic alcoholic pancreatitis; and (iii) 265 control subjects randomly selected from the Verona polling lists and submitted to a complete medical checkup. The variables considered were age at onset of disease, years of drinking and smoking, daily alcohol intake in grams, number of cigarettes smoked daily, and body mass index (BMI). Cases differed from controls in daily grams of alcohol, number of cigarettes smoked and BMI (Mann-Whitney U test, p < 0.00001 for each comparison). Multivariate logistic regression analysis, comparing acute and chronic cases, respectively, versus controls, revealed an increased relative risk of pancreatitis in the two comparisons, associated in both cases with a higher alcohol intake (p < 0.00001) and cigarette smoking (p < 0.00001). No significant interaction between alcohol and smoking was noted, indicating that the two risks are independent. In conclusion, in males a higher number of cigarettes smoked daily seems to be a distinct risk factor in acute and chronic alcoholic pancreatitis.