BACKGROUND/OBJECTIVES:We had developed the Unifying-Autoimmune-Pancreatitis-Criteria (U-AIP) to diagnose autoimmune pancreatitis (AiP) within the M-ANNHEIM classification of chronic pancreatitis. In 2011, International-Consensus-Diagnostic-Criteria (ICDC) to diagnose AiP have been published. We had applied the U-AIP long before the ICDC were available. The aims of the study were, first, to describe patients with AiP diagnosed by the U-AIP; second, to compare diagnostic accuracies of the U-AIP and other diagnostic systems; third, to evaluate the clinical applicability of the U-AIP. METHODS:From 1998 until 2008, we identified patients with AiP using U-AIP, Japanese-, Korean-, Asian-, Mayo-HISORt-, Revised-Mayo-HISORt- and Italian-criteria. We retrospectively verified the diagnosis by ICDC and Revised-Japanese-2011-criteria, compared diagnostic accuracies of all systems and evaluated all criteria in consecutive patients with pancreatitis (2009 until 2010, Pancreas-Outpatient-Clinic-Cohort, n = 84). We retrospectively validated our diagnostic approach in consecutive patients with a pancreatic lesion requiring surgery (Surgical-Cohort, n = 98). RESULTS:Overall, we identified 21 patients with AiP. Unifying-Autoimmune-Pancreatitis-Criteria and ICDC presented the highest diagnostic accuracies (each 98.8%), highest Youden indices (each 0.95238), and highest proportions of diagnosed patients (each n = 20/21, U-AIP/ICDC vs. other diagnostic systems, p < 0.05, McNemar test). In the Pancreas-Outpatient-Clinic-Cohort, seven patients were diagnosed with AiP (n = 6 by U-AIP, n = 1 by Asian-criteria). International-Consensus-Diagnostic-Criteria confirmed the diagnosis in these individuals. Based on partial fulfillment of U-AIP, AiP was initially suspected in 13% (n = 10/77) of remaining patients from the Pancreas-Outpatient-Clinic-Cohort. In the Surgical-cohort, we identified one patient with AiP by U-AIP and ICDC. CONCLUSIONS:Unifying-Autoimmune-Pancreatitis-Criteria revealed a satisfactory clinical applicability and offered an additional approach to diagnose AiP.

Background/Aims: The prevalence and incidence of autoimmune pancreatitis (AiP) in those living in western countries are largely unknown. We aimed to determine the prevalence of AiP among patients with pancreatitis presenting to our tertiary referral center in Mannheim, Germany; and to estimate the incidence of AiP in the Southwest of Germany. Methods: We performed a retrospective cross-sectional analysis and determined the prevalence of AiP in patients with acute pancreatitis (AP) or chronic pancreatitis (CP). Patients (n = 704; alcoholic pancreatitis n = 373, nonalcoholic pancreatitis n = 331) were stratified into the Retrospective-Pancreas-Cohort (RPC, period 1998-2008, n = 534) and the Pancreas-Clinic-Cohort (PCC, periods 2008-2010 and 2013-2014, n = 170, with detailed investigation for features of AiP). Diagnosis of AiP was established by International-Consensus-Diagnostic-Criteria and Unifying-Autoimmune-Pancreatitis-Criteria. Results: In the RPC, the prevalence of AiP was 5.9% (n = 13/221) among individuals with nonalcoholic pancreatitis (n = 1/61 with AP, 1.6%; n = 12/160 with CP, 7.5%). In the PCC, the prevalence of AiP was 9.1% (n = 10/110) among patients with nonalcoholic pancreatitis (n = 2/24 with AP, 8.3%; n = 8/86 with CP, 9.3%), and 1.7% (n = 1/60) among subjects with alcoholic pancreatitis. We estimated the incidence of AiP with 0.29 per 100,000 population each year. Conclusion: The prevalence rate of AiP may account for 9% of patients with nonalcoholic pancreatitis but is almost never observed in patients with alcoholic pancreatitis. The incidence of AiP in Germany appears lower than 1 per 100,000 population.

Background & Aims: Distinguishing between acute on chronic liver failure (ACLF) and decompensated liver cirrhosis is difficult due to a lack of pathological evidence.Methods: A prospective single-center study investigated 174 patients undergoing liver transplantation due to acute decompensation of hepatitis B virus (HBV)-associated liver cirrhosis. Two groups were distinguished by the presence or absence of submassive hepatic necrosis (SMHN, defined as necrosis of 15-90% of the entire liver on explant). Core clinical features of ACLF were compared between these groups. Disease severity scoring systems were applied to describe liver function and organ failure. Serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes were used to study systemic and local inflammatory responses.Results: SMHN was identified in 69 of 174 patients proven to have cirrhosis by histological means. Characteristic features of SMHN were extensive necrosis along terminal hepatic veins and spanning multiple adjacent cirrhotic nodules accompanied by various degrees of liver progenitor cell-derived regeneration, cholestasis, and ductular bilirubinostasis. Patients with SMHN presented with more severely impaired hepatic function, a higher prevalence of multiple organ failure (as indicated by higher CLIF-SOFA and SOFA scores) and a shorter interval between acute decompensation and liver transplantation than those without SMHN (p < 0.01 for all parameters). Further analyzes based on serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes revealed higher levels of anti-inflammatory cytokines in patients with SMHN.Conclusions: SMHN is a critical histological feature of HBV-associated ACLF. Identification of a characteristic pathological feature strongly supports that ACLF is a separate entity in end-stage liver disease. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

?Por que tienden las personas a consumir alcohol? El estudio de nuestros ancestros arroja luz sobre esta cuestion.

Chronic hepatitis C viral infection modulates complement. The aim of this study was to determine whether complement analysis predicts liver inflammation and fibrosis in patients with chronic hepatitis C.50 chronic hepatitis C patients who underwent a liver biopsy were compared to 50 healthy controls and 35 patients with various liver diseases. Total plasma complement activity (CH50) in plasma was diminished in hepatitis C patients suggesting complement activation. This decrease correlated with increased necrosis (r = -0.24, p < 0.05), and patients with levels below the normal range had a higher METAVIR activity score reflecting enhanced inflammation. SC5b-9, a marker of complement activation, correlated with inflammation (r = 0.40, p < 0.05), activity (r = 0.42, p < 0.05), and fibrosis scores (r = 0.49, p < 0.05). Finally, the prevalence of C1q auto-antibodies was higher in hepatitis C patients, and their presence was associated with increased inflammation and seemed to affect fibrosis.We conclude that complement-induced liver inflammation contributes to fibrosis in patients with chronic hepatitis C. (C) 2013 Elsevier Inc. All rights reserved.

The endogenous cannabinoids anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG) are upregulated during liver fibrogenesis and selectively induce cell death in hepatic stellate cells (HSCs), the major fibrogenic cells in the liver, but not in hepatocytes. In contrast to HSCs, hepatocytes highly express the AEA-degrading enzyme fatty acid amide hydrolase (FAAH) that protects them from AEA-induced injury. However, the role of the major 2-AG-degrading enzyme monoacylglycerol lipase (MGL) in 2-AG-induced hepatic cell death has not been investigated. In contrast to FAAH, MGL protein expression did not significantly differ in primary mouse hepatocytes and HSCs. Hepatocytes pretreated with selective MGL inhibitors were not sensitized towards 2-AG-mediated death, indicating a minor role for MGL in the cellular resistance against 2-AG. Moreover, while adenoviral MGL overexpression failed to render HSCs resistant towards 2-AG, FAAH overexpression prevented 2-AG-induced death in HSCs. Accordingly, 2-AG caused cell death in hepatocytes pretreated with the FAAH inhibitor URB597, FAAH(-/-) hepatocytes, or hepatocytes depleted of the antioxidant glutathione (GSH). Moreover, 2-AG increased reactive oxygen species production in hepatocytes after FAAH inhibition, indicating that hepatocytes are more resistant to 2-AG treatment due to high GSH levels and FAAH expression. However, 2-AG was not significantly elevated in FAAH(-/-) mouse livers in contrast to AEA. Thus, FAAH exerts important protective actions against 2-AG-induced cellular damage, even though it is not the major 2-AG degradation enzyme in vivo. In conclusion, FAAH-mediated resistance of hepatocytes against endocannabinoid-induced cell death may provide a new physiological concept allowing the specific targeting of HSCs in liver fibrosis.

Genetic variants in antioxidant pathways might decrease the efficacy of radiation therapy (RT) by suppressing the generation of reactive oxygen species. We studied the association between single nucleotide polymorphisms (SNPs) in the antioxidant gene superoxide dismutase-2 (SOD2) and cancer-specific outcomes after RT.Among 816 prostate cancer patients who received radiation as primary therapy from the Physicians' Health Study and the Health Professionals Follow-up Study, we evaluated the association of 7 tagging SNPs in SOD2 with lethal prostate cancer (death from prostate cancer or distant metastasis among living patients). We sought to validate findings in a separate cohort of 612 prostate cancer patients treated with RT with a greater proportion of intermediate and high-risk Gleason scores at the Dana-Farber Cancer Institute. Genetic effects were analyzed using a codominant model, using the genotype homozygous for the major allele as baseline.Among patients who underwent RT in the test cohort, there was a significant association between 3 of the 7 SOD2 SNPs and lethal prostate cancer: rs6917589 (overall P = .006), rs2758331 (P = .04) and the functional valine to alanine polymorphism in rs4880 (P = .04). These SNPs were not associated with outcome among men who had undergone prostatectomy. The associations were not replicated in the validation cohort.Germline genetic variation in the SOD2 gene might be a predictive biomarker of response to RT for prostate cancer but is not consistently associated with outcome after RT across prostate cancer cohorts with different clinical characteristics.

The endocannabinoid system is a crucial regulator of hepatic fibrogenesis. We have previously shown that the endocannabinoid anandamide (AEA) is a lipid mediator that blocks proliferation and induces death in hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver, but not in hepatocytes. However, the effects of other endocannabinoids such as N-arachidonoyl dopamine (NADA) have not yet been investigated. The NADA-synthesizing enzyme tyrosine hydroxylase was mainly expressed in sympathetic neurons in portal tracts. Its expression pattern stayed unchanged in normal or fibrotic liver. NADA dose dependently induced cell death in culture-activated primary murine or human HSCs after 2-4 h, starting from 5 μM. Despite caspase 3 cleavage, NADA-mediated cell death showed typical features of necrosis, including ATP depletion. Although the cannabinoid receptors CB1, CB2, or transient receptor potential cation channel subfamily V, member 1 were expressed in HSCs, their pharmacological or genetic blockade failed to inhibit NADA-mediated death, indicating a cannabinoid-receptor-independent mechanism. Interestingly, membrane cholesterol depletion with methyl-β-cyclodextrin inhibited AEA- but not NADA-induced death. NADA significantly induced reactive oxygen species formation in HSCs. The antioxidant glutathione (GSH) significantly decreased NADA-induced cell death. Similar to AEA, primary hepatocytes were highly resistant against NADA-induced death. Resistance to NADA in hepatocytes was due to high levels of GSH, since GSH depletion significantly increased NADA-induced death. Moreover, high expression of the AEA-degrading enzyme fatty acid amide hydrolase (FAAH) in hepatocytes also conferred resistance towards NADA-induced death, since pharmacological or genetic FAAH inhibition significantly augmented hepatocyte death. Thus the selective induction of cell death in HSCs proposes NADA as a novel antifibrogenic mediator.

The WHO ranks smoking and alcohol consumption as the first and third leading causes of the global burden of disease in industrialized countries, using disability-adjusted life years (DALYs) as a combined measure of premature death and disability. Smoking is responsible for 12.2% of all DALYs and alcohol consumption for 9.2%. For example in Germany, annually 110,000–140,000 humans die prematurely because of cigarette smoking and 40,000 because of alcohol drinking. In Europe and the USA, more than 20% of all hospitalized men and more than 9% of all hospitalized women suffer from alcohol-associated diseases. In Germany, about 2.0 million people in the age group 18–64 years (3.8% of all Germans) are alcohol abusers and 1.3 million people (2.4%) are alcohol-dependent. Alcohol can cause acute as well as chronic damage in nearly all body organs. Smoking damages also nearly every human body organ and is worldwide the most important single preventable health risk factor as well as the main cause for premature mortality in industrial countries. One third of the adult Germans as well as of the world population are active smokers; men smoke more frequently than women (34.0 vs. 25.1%). In this review a short overview will be given on the most important deleterious effects of alcohol and smoking. The most recent data about the pathophysiological relevance of non-alcoholic compounds of alcoholic beverages will also be discussed.

Chaired by H.E. Blum, Freiburg/Germany and C. McClain, Louisville/USA 14:40-15:10 H. Witt, Weihenstephan/Germany Genetics of pancreatitis: a guide for clinicians 15:10-15:40 R.M. Schmid, München/Germany Alcohol and pancreatic cancer: a pooled analysis of fourteen cohort studies 15:40-16:10 F. Bendtsen, Kopenhagen/Denmark Long-term, clinical follow-up in fatty liver patients 16:10-16:40 Break

Aims: We and others have previously shown, that the hepatic endocannabinoid (EC) system becomes activated during fibrogenensis. In particular, the expression of cannabinoid receptors and levels of ECs (anandamide, AEA; 2-arachydonoyl glycerol, 2-AG) are upregulated. However, the mechanisms that lead to the increased levels of ECs during liver fibrogenensis are unknown. AIM: We sought to analyse the hepatic expression and activity of the major AEA-degrading enzyme fatty acid amide hydrolase (FAAH) and the 2-AG-degrading enzyme monoacyl glycerol lipase (MGL) in normal and fibrotic mouse livers at different timepoints after bile duct ligation (BDL) in correlation to intrahepatic EC levels. METHODS: AEA and 2-AG were measured by liquid chromatography/mass spectrometry in liver tissue from male BALB/C mice 2, 5, 7 and 14 days after BDL or sham operation (n=4 each). Alpha-SMA expression was analysed by Western blot. FAAH and MGL mRNA or protein expression were determined by Real Time PCR and Western blot. Enzymatic FAAH and MGL activities in liver tissue were measured colorimetrically. RESULTS: As a sign of hepatic fibrogenesis, alpha-SMA expression significantly increased 5, 7 and 14 days after BDL. Hepatic AEA and 2-AG levels were increasingly elevated up to 2 to 2.5-fold 14 days (p<0.05) after BDL. The mRNA and protein expression of FAAH and MGL decreased significantly during the BDL timecourse. Enzymatic EC degradation activity of FAAH and MGL also decreased significantly during fibrogenesis. Linear regression analysis revealed a significant correlation between the increase in EC levels and the decreased expression and activity of FAAH or MGL, respectively. CONCLUSION: Elevated EC levels in fibrotic liver are due to decreased expression and activity of EC-degrading enzymes FAAH and MGL. Modification of expression or activity of EC-degrading enzymes may represent a tool to modify the regulation of the endocannabinoid tone in the injured or fibrotic liver.