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Genetic mutations in various pancreatic enzymes or their counteracting proteins have been linked to chronic pancreatitis. In particular, variants in the genes encoding pancreatic lipase (PNLIP) and carboxyl ester lipase (CEL) have been associated with pancreatitis. Therefore, we investigated pancreatic phospholipase A2 (PLA2G1B) as a promising candidate gene in patients with chronic pancreatitis.We analyzed all coding exons and adjacent intronic regions of PLA2G1B in 416 German patients with non-alcoholic chronic pancreatitis (NACP) and 186 control subjects by direct DNA sequencing.We detected 2 frequent synonymous variants in exon 3: c.222TC (p.Y74 = ) and c.294GA (p.S98 = ). The genotype and allele frequencies of these variants were similar between patients and controls (c.222 TC: 9.6% in NACP vs. 9.7% in controls; c.222CC: 0.2% in NACP vs. 0% in controls; c.294 GA: 31.3% in NACP vs. 28.0% in controls; c.294AA: 2.4% in NACP vs. 1.1% in controls). All p-values were non-significant. In addition, we found one synonymous variant, c.138CT (p.N46 = ) and one non-synonymous variant, c.244AG (p.S82G), in a single case each.Our results suggest that genetic alterations in PLA2G1B do not predispose to the development of non-alcoholic chronic pancreatitis.

Purpose Patients with a first attack of acute pancreatitis (AP) can develop recurrent acute pancreatitis (RAP). Hence, this study aimed to investigate the clinical features of the disease and the risk factors for RAP. Methods We performed a retrospective study of 522 patients from Jan 1 to Dec 31, 2006. All patients with AP were followed for 36 months. The primary end point was the rate of RAP. The secondary end points were the risk factors that were evaluated by Cox regression analysis. The cumulative risk of RAP was assessed using Kaplan-Meier analysis. Results 56 of the 522 patients (10.7%) developed RAP. Among those RAP patients, 37 (7.1%) experienced one relapse, 10 (1.9%) experienced two relapses, and 9 (1.7%) experienced three or more relapses. Univariate analysis indicated that age (p = 0.016), male sex, etiology of AP (p = 0.001), local complications (p = 0.001) and Length of stay (LOS) (p = 0.007) were associated with RAP. Multivariate analysis with the Cox proportional hazards model showed that male sex (HR = 2.486, 95% CI, 0.169–0.960, p = 0.04), HTG-associated etiology (HR = 5.690, 95% CI, 2.138–15.146, p = 0.001), alcohol-associated etiology (HR = 5.867, 95% CI, 1.446–23.803, p = 0.013) and current local complications at index admission (HR = 8.917, 95% CI, 3.650–21.789, p = 0.001) were significant independent risk factors for RAP. Conclusions A first attack of AP led to RAP in 10.7% of patients within 3 years. Male sex was significantly associated with RAP. The etiologies of alcohol and HTG and local complications were the strongest risk factors for recurrent disease. Patients with these characteristics should be given special attention and followed-up closely.

Contains fulltext : 229360.pdf (Publisher’s version ) (Closed access) BACKGROUND: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies. METHODS: We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis. RESULTS: We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10(-5)) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis. CONCLUSIONS: Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.

The natural course of chronic pancreatitis(CP) and its complications has been inadequately explored. We aimed to describe the natural history and factors affecting the progression of alcoholic(ACP), idiopathic juvenile(IJCP) and idiopathic senile(ISCP) variants of CP.This study was a retrospective analysis from a prospectively maintained database of patients with CP following up at a tertiary care centre from 1998 to 2019. Cumulative rates of pain resolution, diabetes, steatorrhea, pseudocysts and pancreatic cancer were computed using Kaplan-Meier analysis, and the factors affecting their incidence were identified on multivariable-adjusted Cox-proportional-hazards model.A total of 1415 patients were included, with 540(38.1%) ACP, 668(47.2%) IJCP and 207(14.6%) ISCP with a median follow-up of 3.5 years(Inter-quartile range: 1.5-7.5 years). Diabetes occurred at 11.5, 28 and 5.8 years(p 0.001) while steatorrhea occurred at 16, 24 and 18 years(p = 0.004) after onset for ACP, IJCP and ISCP respectively. Local complications including pseudocysts occurred predominantly in ACP(p 0.001). Ten-year risk of pancreatic cancer was 0.9%, 0.2% and 5.2% in ACP, IJCP and ISCP, respectively(p 0.001). Pain resolution occurred more frequently in patients with older age of onset[Multivariate Hazard Ratio(HR):1.7(95%CI:1.4-2.0; p 0.001)], non-smokers[HR:0.51(95%CI:0.34-0.78); p = 0.002] and in non-calcific CP[HR:0.81(0.66-1.0); p = 0.047]. Occurrence of steatorrhea[HR:1.3(1.03-1.7); p = 0.028] and diabetes[HR:2.7(2.2-3.4); p 0.001] depended primarily on age at onset. Occurrence of pancreatic cancer depended on age at onset[HR:12.1(4.7-31.2); p 0.001], smoking-history[HR:6.5(2.2-19.0); p 0.001] and non-alcoholic etiology[HR:0.14(0.05-0.4); p 0.001].ACP, IJCP and ISCP represent distinct entities with different natural course. Age at onset of CP plays a major prognostic role in all manifestations, with alcohol predominantly causing local inflammatory complications.

In Finland the incidence of chronic pancreatitis (CP) is high compared to that in most European countries. Recent epidemiological data is lacking. Our aim was to investigate the current epidemiologic and behavioural data on CP patients in Finland.CP patients according to M-ANNHEIM criteria in Tampere University Hospital (TAUH) during 2014-2015 were included. Aetiology, time from diagnosis, pancreatic function, treatment, complications, smoking, alcohol consumption (AUDIT) and quality of life (QoL) (QLQ C30, PAN26) were gathered.235 CP patients (57 (26-88) years, 65% men) were included. Time since diagnosis was 5.5 (1-41) years. Aetiology was alcohol in 67%, and smoking contributed in 54%. Of these patients 78% continued smoking and 58% continued to consume alcohol even after CP diagnosis. CP related complications were common. Pseudocysts were more common in alcohol related CP than in non-alcohol related CP (60% vs. 38%, p 0.05). Reported QoL and pain were worse in the CP patients than in controls. Alcohol consumption differed from that of the Finnish population; the CP patients were either total abstainers or heavy alcohol consumers.CP constitutes a great burden on the health care system and on the patients. The patients frequently develop complications and symptoms and their QoL is inferior to that of controls. The most important measure to halt the progression of CP would be to prevent acute phases and for patients to stop smoking, which does not happen in many CP patients. It would be beneficial to increase awareness among CP patients and medical professionals.

Pancreatic ducts secrete 2.5 l of alkaline, HCO 3 − -rich fluid daily which greatly contributes to the homeostasis of the pancreas. Ducts are also important in the pathophysiology of the pancreas; alteration of ductal function can lead to severe diseases such as cystic fibrosis and chronic pancreatitis. The role of pancreatic ducts in the development of acute pancreatitis has only been uncovered recently. Pancreatitis inducing agents like bile acids and ethanol dose-dependently affect pancreatic ductal secretion; low concentrations stimulate, whereas high concentrations inhibit secretion. The majority of the review will focus on the central role of cystic fibrosis transmembrane conductance regulator (CFTR), a critical protein in the regulation of ductal secretion, in the pathogenesis of acute pancreatitis which is highlighted by numerous investigations. Downregulation of CFTR expression results in increased severity of acute pancreatitis in mice. Furthermore, human genetic studies have demonstrated statistically significant association of CFTR mutations with acute recurrent pancreatitis. Overall, the data support the involvement of pancreatic ducts in the pathogenesis of acute pancreatitis.

Background The cellular microenvironment plays an important role in the regulation of homoeostasis and is a source of potential biomarkers and drug targets. In a genome-wide analysis the extracellular proteins that bind to heparin (HBPs) have been shown to form highly modular and interconnected extracellular protein regulatory networks. Using a systems biology approach, we have investigated the role of HBP networks in the normal pancreas and pancreatic digestive diseases. Methods Lists of mRNAs encoding for HBPs associated with the normal pancreas (NP), acute pancreatitis (AP), chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) were obtained using public databases and publications. Networks of the putative protein interactomes derived from mRNA expression data of HBPs were built and analysed using cluster analysis, gene ontology term enrichment and canonical pathways analysis. Results The extracellular heparin-binding putative protein interactomes in the pancreas were better connected than their non heparin-binding counterparts, having higher clustering coefficients in the normal pancreas (0.273), acute pancreatitis (0.457), chronic pancreatitis (0.329) and pancreatic ductal adenocarcinoma (0.269). ‘Hepatic Fibrosis/Hepatic Stellate Cell Activation’ appears to be a significant canonical pathway in pancreatic homoeostasis in health and disease with a large number of important HBPs. Conclusions Our analyses clearly demonstrate that HBPs form disease-specific and highly connected networks that can be explored for potential biomarkers and as collective drug targets via the modification of heparin binding properties.

Background: Internal pancreatic fistula (IPF) is a well-recognized complication of pancreatic diseases. Although there have been many reports concerning IPF, the therapy for IPF still remains controversial. We herein report our experiences with endoscopic transpapillary pancreatic stent therapy for IPF and evaluate its validity. Method: Six patients with IPF who presented at our department and received endoscopic transpapillary pancreatic stent therapy were investigated, focusing on the clinical and imaging features as well as treatment strategies, the response to therapy and the outcome. Results: All patients were complicated with stenosis or obstruction of the main pancreatic duct, and in these cases the pancreatic ductal disruption developed distal to the areas of pancreatic stricture. The sites of pancreatic ductal disruption were the pancreatic body in five patients and the pancreatic tail in one patient. All patients received endoscopic stent placement over the stenosis site of the pancreatic duct. Three patients improved completely and one patient improved temporarily. Finally, three patients underwent surgical treatment for IPF. All patients have maintained a good course without a recurrence of IPF. Conclusion: Endoscopic transpapillary pancreatic stent therapy may be an appropriate first-line treatment to be considered before surgical treatment. The point of stenting for IPF is to place a stent over the stenosis site of the pancreatic duct to reduce the pancreatic ductal pressure and the pseudocyst's pressure., Pancreatology, 13(6), pp.621-624; 2013

Background Severe acute pancreatitis (SAP) is a serious disease associated with alcoholism and has a high mortality rate. Effective treatments have not been established. Methods A 58-year-old man was admitted due to alcoholic SAP. Endoscopic retrograde cholangiopancreatography revealed pancreatic calculi at the pancreas head and a stricture in the pancreatic duct from the pancreas head to the body. Endoscopically, nasopancreatic drainage (NPD) was placed through the minor papilla to the pancreas tail beyond the stricture. Results Pancreatic juice culture was positive for Streptococcus and Enterobacter. The day after NPD, upper abdominal pain was relieved. After changing NPD to a pancreatic stent, the patient was discharged on day 21 post-NPD. Conclusion Alcoholic SAP may reflect aggravation of chronic pancreatitis. The possibility of acute bacterial inflammation should be considered in all cases of chronic alcoholic pancreatitis who present with severe features of inflammation, even in the early stages of an attack. Treatment of this subset of cases by drainage could be of great importance and NPD may be the preferred method.

Supplementation of n-3 long-chain polyunsaturated fatty acids (LCPUFA) is considered as adjuvant therapy in acute pancreatitis. We investigated plasma fatty acid status in chronic pancreatitis (CP).Patients with alcoholic CP (n = 56, gender: 33/23 male/female, age: 60.0 [14.0] years (median [IQR]), who reported giving up alcohol consumption several years ago and 51 control subjects were included into the study. The fatty acid composition of plasma phospholipids (PL), triacylglycerols (TG) and sterol esters (STE) was analyzed.The sum of monounsaturated fatty acids was significantly higher in patients with CP than in controls (PL: 12.83 [3.35] vs. 12.20 [1.95], TG: 40.51 [6.02] vs. 37.52 [5.80], STE: 20.58 [7.22] vs. 17.54 [3.48], CP vs. control, % weight/weight, median [IQR], p0.05). Values of arachidonic acid were significantly lower in patients with CP than in controls (PL: 10.57 [3.56] vs. 11.66 [3.25], STE: 8.14 [2.63] vs. 9.24 [2.86], p0.05). Values of eicosapentaenoic acid and docosahexaenoic acid did not differ and there was no difference in the ratio of n-3 to n-6 LCPUFA.Our present data do not furnish evidence for the supplementation of n-3 LCPUFA to the diet of CP patients in relatively good clinical condition.

The mechanism of alcoholic pancreatitis is still unknown. It is of special interest why only about 5% of all alcoholics develop an episode of pancreatitis. We evaluated the role of long-term alcohol intake in the pathogenesis of alcoholic pancreatitis in rats.To evaluate the effect of long-term alcohol intake, rats were fed either a Lieber-DeCarli control diet (CD) or a Lieber-DeCarli alcohol diet (AD) for 6 weeks. Then, rats were infused over 2 h with either Ringer's solution (CO) or ethanol (E). In additional animals, alcoholic pancreatitis was induced by ethanol combined with hyperlipidemia and temporary pancreatic duct obstruction (EFO). Controls received Ringer's solution combined with hyperlipidemia and temporary pancreatic duct obstruction (RFO). Intravital microscopy (pancreatic perfusion and leukocyte adhesion), alcohol concentrations, amylase, lipase, cholesterine and triglyceride levels in plasma, myeloperoxidase activity and histology were evaluated at different time intervals.In those animals which received the Lieber-DeCarli control diet, capillary perfusion was reduced in the E group and further reduced in the EFO group as compared to the controls (CO, RFO; p0.01). Leukocyte adhesion was significantly increased in rats receiving E (p0.01), and was further increased in the combination group EFO (p0.01). EFO induced histologically evident acute pancreatitis. The additional administration of a long-term alcohol diet further increased microcirculatory disturbances and pancreatic injury significantly (EFO-ADEFO-CD).This study shows that alcoholic pancreatitis is induced by the combination of ethanol and individual cofactors. Chronic alcohol abuse intensifies these changes. Therefore, long-term alcohol intake seems to be a major factor in the pathogenesis of alcoholic pancreatitis.

Resistin and visfatin, hormones produced by adipose tissue, have pro-inflammatory potential; however, their role in acute pancreatitis (AP) has been investigated only rarely.The study group comprised 32 patients with alcoholic AP and 30 controls. In all cases AP was classified as C according to Balthazar's CT score and as severe according to Ranson's criteria. The serum level of visfatin, resistin, and interleukin(IL)-8 immunoassays were measured by ELISA on admission and on the third and fifth day of hospitalization.On the admission day serum resistin and IL-8 concentrations in AP patients were significantly higher than in controls and they further increased on the third and fifth day of hospitalization. On the admission day serum visfatin levels in AP patients were significantly higher than in controls and further increased on the third day of hospitalization. On the fifth day the levels decreased; however, they were still higher than on admission. The correlation between visfatin and resistin as well as between C-reactive protein and visfatin, resistin and IL-8 levels has been found.In the course of AP, visfatin and resistin levels increase in parallel with C-reactive protein. We speculate that those parameters may provide an additional tool for the prognosis and monitoring of AP. and IAP.

Obesity is a known risk factor for severe acute pancreatitis (AP). Since alcoholic chronic pancreatitis (ACP) is closely linked to alcoholic AP, overweight before disease onset might impact on incidence and outcome of ACP, and represent an additional risk factor for ACP. This issue has not been investigated, despite discussions on the 'hypercaloric-high-fat' hypothesis as an additional risk factor for ACP for many years.The study is part of our prospective long-term study of a large, mixed, medical/surgical series of ACP patients. All cooperative patients were studied according to a protocol regarding clinical symptoms, physical status, routine laboratory tests, pancreatic function and pancreatic morphology (e.g. calcification) at yearly follow-ups. Our study includes 227 ACP patients with recorded body mass index (BMI) before disease onset followed up on average for 18 years from chronic pancreatitis (CP) onset.Males predominated (89.9%), age at onset averaged at 36 years, and exocrine insufficiency (97.4%) and calcification (88.1%) developed in virtually all patients. Surgery for B-type pain was performed in 57.7%, and death occurred in 62.8%. Overweight before disease onset was found in 54.2% (obesity in 15.0%) compared to 37.7% (3.1%) from a contemporary male control population. The highest BMI before disease onset did not impact on some major variables of ACP such as gender, age, progression of exocrine insufficiency, diabetes and calcification, and mortality from CP, except for a delayed progression rate of ACP indices in the surgical series.Overweight before disease onset appears to be another risk factor for ACP, supporting the 'hypercaloric-high-fat' hypothesis. and IAP.

Background/Aims: Mutations in the PRSS1 and the SPINK1 genes have variably been associated with alcohol-related, idiopathic and hereditary chronic pancreatitis (CP). The aim of this study was to determine for the first time the significance of PRSS1, SPINK1 mutations and genetic variants of AAT in a group of Spanish patients with CP. Methods: 104 consecutive patients with CP were included, as well as 84 healthy control subjects. The R122H and N29I mutations in the PRSS1 gene, the N34S mutation in the SPINK1 gene and PiS and PiZ mutations in the AAT gene were analyzed by RFLP-PCR methods. Results: No R122H mutation was found in the PRSS1 gene, and N29I mutation was detected in 7.7% of CP patients. A N29I mutation was observed in 3.9% of patients with alcohol-related pancreatitis (ACP). A total of 5.8% of CP patients were identified with the N34S mutation. Genotype MS, SS and MZ were detected in 18.3, 3.8 and 1.3% of CP patients, respectively. Conclusion: The percentage of N29I mutations in ACP patients was higher than that reported in other studies, while the percentage of N34S and AAT mutations in ACP and idiopathic CP patients was similar. Copyright (C) 2009 S. Karger AG, Basel and IAP

Acute alcoholic pancreatitis (AAP) recurs in up to half of the patients, continuous alcohol consumption being an important risk factor. Changes in pancreatic function and morphology after acute pancreatitis have been characterized previously, but their association with later recurrences has not been adequately studied.In this prospective follow-up study, the pancreatic function of 54 patients (47 males and 7 females) with a median age of 49 years (range 25-71) and morphology (35 patients) were evaluated. Pancreatic morphology was evaluated by secretin-stimulated magnetic resonance pancreatography (SMRP). Patients were evaluated early (baseline) and at 2 years after the first episode of AAP. In order to evaluate later recurrences, the patients were followed for a median of 47 (range 28-66) months.Of the 46 patients without previous diabetes, 17 patients (37%) developed impaired glucose metabolism during the 2 years following the first AAP. The prevalence of exocrine dysfunction decreased from 39% at baseline to 9% at 2 years. Of the patients with severe pancreatitis (n = 13, 24%), 31% had elevated glycosylated haemoglobin levels compared to 7% in patients with mild pancreatitis [p = 0.05, odds ratio (OR): 5.5, 95% confidence interval (CI): 1.04-29.0]. Twenty percent (7/35) of the patients had changes consistent with chronic pancreatitis on baseline SMRP, which persisted in all cases. Of the 29% patients with acute changes on baseline SMRP, the acute changes resolved in 50% and chronic pancreatitis was detected in the remaining 50% at 2 years. Development of chronic changes did not depend on continued alcohol consumption, as it was also found in 3 patients practising complete abstinence following their first attack of AAP. The presence of a chronic pseudocyst at 2 years predicted pancreatitis when compared to patients lacking pseudocyst formation: 4 (80%) versus 5 (17%) (p = 0.01, OR: 20.0, 95% CI: 1.83-219).The severity of the first episode of AAP was associated with deteriorated diabetes control, but not with pancreatic exocrine dysfunction at 2 years. The number of patients with chronic changes on SMRP increased independently of alcohol consumption. Chronic pseudocyst formation seen on SMRP 2 years after AAP was significantly associated with recurrence of pancreatitis.

Pancreas susceptibility to alcohol is variable and only 5-10% of chronic alcohol abusers develop chronic pancreatitis; the role of genetic factors in this process is unknown. The CFTR gene encodes a protein that acts on epithelial cells and plays a key role in normal exocrine pancreatic function.This study investigated the frequency of polymorphisms in intron 8 of the CFTR gene in patients with alcoholic chronic pancreatitis. Three groups of patients were studied: group A - 68 adult alcoholics with a diagnosis of chronic pancreatitis; group B - 68 adult alcoholics without pancreatic disease or liver cirrhosis and group C - 104 healthy nonalcoholic adults.T5/T7 genotype was more frequent in group A (11.8%) than in group B (2.9%) (p = 0.0481), and there was no statistical difference when groups A and C (5.8%) were compared (p = 0.1317). The haplotype combination (TG)10-T7/(TG)11-T7 was more frequent in groups B (23.5%) and C (20.2%) than in group A (7.3%) (p = 0.0080 and 0.0162).There are differences when these three groups are compared and individuals with T5/T7 genotype might have a greater risk of developing chronic pancreatitis when they become chronic alcoholics.

This paper provides a summary of the effects of alcohol abuse on the pathobiologic responses that occur during acute and chronic pancreatitis considering both the human disease and animal/tissue models. The effects are multiple and include ones on cell death leading to necrosis; on inflammation resulting in a sensitized response to pancreatic stress; and fibrosis through effects of ethanol on pancreatic stellate cells and the plasminogen system. Although the effects of alcohol are multiple and complex, it is likely that a combination of a few key effects on these pathobiologic responses drive the increased sensitivity of the pancreas to acute pancreatitis with pancreatic stress and the promotion of chronic pancreatitis with pancreatic injury occurring during acute pancreatitis.

No study on bioclinical criteria predicting a biliary origin for acute pancreatitis has included endosonography as a reference examination. Re-examination of bioclinical parameters deserves consideration in the era where other causes are known (e.g. hereditary, autoimmune).To determine the performance of bioclinical markers in predicting a biliary origin of acute pancreatitis where the diagnosis of biliary lithiasis was established or ruled out using endosonography. Only patients with a first acute episode of pancreatitis were included.213 patients (male: 55%; median age: 56 years) were prospectively included in 14 centres. Causes of acute pancreatitis were: biliary (62%), alcoholic (25%), other (13%). Delay between symptom-onset and admission was48 h in 80%. Endosonography was the sole method establishing the diagnosis of biliary pancreatitis in 15% of patients. At univariate analysis, age, female sex, declared alcohol consumption, elevated aspartate and alanine transaminases on admission, gammaglutamyl transferase, alkaline phosphatase, total bilirubin, lipase, mean corpuscular volume were predictive of a biliary origin. Only age (p0.0001), sex (p0.0008) and alanine transaminase (p0.0004) remained significant at multivariate analysis. At age 50, the respective sensitivity and specificity were 73 and 65%. With an elevated alanine transaminase at 2 times the upper limit of normal range, the respective sensitivity and specificity were 74 and 84%. The probability of a biliary origin of acute pancreatitis could be estimated by the following formula: = 1/1 + exp(4.6967 - 0.0656 x age + 1.1208 x sex - 0.6909 x alanine transaminase).When endosonography is performed to confirm or exclude a biliary origin of acute pancreatitis, age, sex and alanine transaminase at admission are the only factors predictive of a biliary cause.

Bleeding is a rare complication of pancreatic pseudocyst. We describe an exceptional case of necrotizing pseudocyst with mediastinal extension providing cataclysmic oesophageal haemorrhage. The patient was successfully treated by adequate endoscopic, radiological and surgical management.