Search

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.

Alcohol use is a common cause of recurrent acute pancreatitis. Thus, guidelines recommend providing alcohol prevention resources during hospitalization. There is limited data on the real-world implementation of this recommendation. We aimed to assess how often inpatients admitted with alcohol-induced acute pancreatitis (AAP) receive counseling and to determine the impact of counseling on readmissions for AAP.We retrospectively studied patients admitted with AAP at a tertiary care center from 2008 to 2018. We compared demographics, clinical features, and outcomes in patients who did and did not receive counseling. Outcomes studied were the proportion of patients with AAP receiving counseling, and readmission rates for AAP at 30 days and 1 year.A total of 243 patients with AAP were identified, of which 115 had inpatient alcohol counseling (47%). Demographic data were comparable between the 2 groups. Fewer patients receiving alcohol counseling were readmitted at 30 days compared with patients not receiving counseling (19.3% vs. 31.2%, P =0.048). At 1 year, the 2 groups had similar readmission rates. On multivariate analysis, patients who received counseling were half as likely to be readmitted in 30 days compared with those who did not receive counseling [odds ratio=0.52 (0.27, 0.98), P =0.046].We note that50% of patients receive alcohol counseling. Patients receiving alcohol counseling were less likely to be readmitted at 30 days, inferring possible value in the intervention provided. Similar readmission rates at 1 year suggest that the single intervention may not have a durable effect on alcohol prevention.

The aim of this study was to determine if hypophosphatemia is more common in patients with severe alcohol-induced acute pancreatitis (AAP).This is a retrospective, single institution, cohort study that analyzed 147 patients admitted to the hospital for AAP. Multivariate logistic regression was used to determine if hypophosphatemia would be related to clinical outcomes of disease severity.Hypophosphatemia was more common in patients with severe AAP at admission; in addition, all patients with severe AAP (100%) eventually developed hypophosphatemia during admission, relative to those with mild (43%) and moderately severe (54%) AAP. The magnitude of the lowest phosphate measurement obtained during admission was lower in patients with severe AAP (mean, 1.5 mg/dL, standard deviation [SD], 0.5 mg/dL) relative to those with mild (mean, 2.6 mg/dL; SD, 0.9 mg/dL) and moderately severe (mean, 2.3 mg/dL; SD, 0.9 mg/dL) AAP (P0.001). Finally, patients who developed hypophosphatemia during admission were more likely to require intensive care unit admission (P0.001), vasopressors (P = 0.01), or intubation (P = 0.003).Hypophosphatemia is more common and of greater magnitude in patients admitted to the hospital with severe AAP. In addition, patients with severe AAP who develop hypophosphatemia during admission are more likely to have poorer clinical outcomes.

Summary Introduction Pancreatic ascites (PA) is an unusual and little studied complication of chronic alcoholic pancreatitis. Management is complex and is based mainly on empirical data. The aim of this retrospective work was to analyse the management of PA at our centre. Patients and methods A total of 24 patients with PA complicating chronic alcoholic pancreatitis were managed at the Lille University Hospital between 2004 and 2018. Treatment was initially medical and then, in case of failure, interventional (endoscopic, radiological and/or surgical). Data regarding epidemiology, therapeutic and follow-up data were collected retrospectively. Results Twenty-four patients were analysed; median follow-up was 18.5 months [6.75–34.25]. Exclusively medical treatment was effective in three of four patients, but, based on intention to treat, medical therapy alone was effective in only two out of 24 patients. Of 17 patients treated endoscopically, treatment was successful in 15 of them. Of the 15 who underwent surgery, external surgical drainage was effective in 13. Multimodal treatment, initiated after 6.5 days [4–13.5] of medical treatment, was effective in 12 out of 14 patients. In total, 21 patients were successfully treated (87%) with a morbidity rate of 79% and a mortality rate of 12.5% (n = 3). Conclusion PA gives rise to significant morbidity and mortality. Conservative medical treatment has only a limited role. If medical treatment fails, endoscopic and then surgical treatment allow a favourable outcome in more than 80% of patients.

The aim of this study was to determine if the quick Sepsis-Related Organ Failure Assessment (qSOFA) score assessed at and 48 hours after admission is prognostic for alcohol-induced acute pancreatitis (AAP) severity.This is a retrospective cohort review study of 161 patients admitted to a single academic hospital in Houston, TX, with the diagnosis of AAP. Receiver operator characteristics analysis and logistic regression were used to assess the diagnostic accuracy and prognostic ability of the qSOFA score.A qSOFA score of 2 or higher at and 48 hours after admission had a specificity of 94% or greater and sensitivity of 33% or higher for pancreatitis severity and need for intensive care admission, intubation, or vasopressors. The qSOFA score at and 48 hours after admission was prognostic of intensive care unit admission by an adjusted odds ratio of 48.5 (95% confidence interval [CI], 6.4-1013.3; Plt; 0.001) and 18.8 (95% CI, 2.2-467.3; Plt; 0.05), respectively. The qSOFA score at admission was prognostic of severe pancreatitis by an adjusted odds ratio of 35.3 (95% CI, 7.2-224.3; Plt; 0.001).A qSOFA score of 2 or higher is highly specific and prognostic of multiple clinical outcomes both at and 48 hours after admission in patients with AAP.

Context.—In the last 2 decades there has been significant progress in typing and recognition of pancreatitis, a necroinflammatory and fibroinflammatory process of multifactorial origin.Objective.—To present the current state of pathology and pathogenesis of alcohol-associated pancreatitis, including paraduodenal pancreatitis. In the context of the most important epidemiologic, clinical, and radiologic features, the related macroscopic changes and histopathologic characteristics are addressed.Data Sources.—In acute pancreatitis we discuss the pathologic findings that distinguish mild from severe pancreatitis and highlight autodigestive fat necrosis as the initial morphologic damage. In chronic pancreatitis we present a histologic staging system that describes the damage patterns as a necrosis-fibrosis sequence that takes place during the development of early to advanced and end-stage chronic pancreatitis. In paraduodenal pancreatitis the anatomic peculiarities are related to the sequence of morphologic changes that are correlated to the most important imaging findings. Pathogenetically, we discuss the role of alcohol overconsumption in triggering autodigestive fat necrosis in the pancreas, the repair of which results in a pancreas-transforming fibroinflammatory process.Conclusions—Whereas in acute pancreatitis there are no lesions that are diagnostic for alcohol overconsumption and that exclude other etiologies such as gallstone disease or drugs, the sequence of damage patterns in chronic pancreatitis are strongly related to the effect of alcohol overconsumption and allow in many cases the distinction from hereditary, autoimmune, or obstructive pancreatitis. Paraduodenal pancreatitis can be considered a special manifestation of alcoholic pancreatitis.

Background The incidence of acute pancreatitis (AP) is characterized by circannual and geographical variation. The aim of this study was to describe seasonal variation and trends in hospitalizations for AP in the USA with respect to AP etiology. Methods The Nationwide Inpatient Sample data (2000–2016) from the Healthcare Cost and Utilization Project were used. The study population included all primary hospitalizations for AP. Biliary AP (BAP) and alcohol-induced AP (AAP) were distinguished by diagnostic and procedural ICD codes. Seasonal trend decomposition was performed. Results There was a linear increase in annual incidence (per 100 000 population) of AAP in the USA (from 17.0 in 2000 to 22.9 in 2016), while incidence of BAP, equaled 19.9 in 2000, peaked at 22.1 in 2006 and decreased to 17.4 in 2016. AP incidence demonstrated 18% annual incidence amplitude with summer peak and winter trough, more prominent in AAP. In 2016, within AAP, the highest incidence (per 100 000 population) was noted among African-Americans (up to 50.4), followed by males aged 56–70 years (26.5) and Asians of low income (25.5); within BAP, above the average incidence was observed in Hispanic (up to 25.8) and Asian (up to 25.0) population. The most consistent and rapid increase in AP incidence was noted in males aged 56–70 years with an alcoholic etiology (average 6% annual incidence growth). Conclusions The incidence and annual trends of AP vary significantly among demographic and socioeconomic groups and this knowledge may be useful for the planning of healthcare resources and identification of at-risk populations.

Background/Objectives: In chronic pancreatitis (CP), progressive fibrosis of the pancreas leads to exocrine and endocrine insufficiency and, finally, to pancreatic burnout. Alcohol consumption is associated with fibrosis in the pancreas and the liver, and the activation of stellate cells plays a central role in the induction of fibrosis in both organs. However, the relationship between pancreatic burnout and liver cirrhosis (LC) is still poorly understood in patients with alcoholic CP (ACP). Methods: We performed a single-center, retrospective, cross-sectional study with 537 CP patients. We analyzed the clinical presence of early and advanced pancreatic burnout and stated LC in cases of typical alterations in histology, liver stiffness measurement, cross-sectional imaging, or ultrasound. We analyzed further clinical parameters. Results: The frequency of advanced pancreatic burnout was 6.5% for ACP (20/306) and 4% for non-ACP (8/206; p = 0.20; χ2 test). Advanced pancreatic burnout was not associated with the amount of alcohol consumption (p = 0.34) but with the disease duration (p = 0.0470) and rate of calcification (p = 0.0056). Furthermore, advanced pancreatic burnout was associated with LC (p < 0.0001) but cannot be explained by the amount of alcohol consumption. In ACP with alcohol consumption >80 g/day, an isolated LC was significantly more frequently detectable (14%, without pancreatic burnout) than an isolated advanced pancreatic burnout (1%, without LC). These results were confirmed by multivariable analyses. Conclusions: We identified a close association between LC and pancreatic burnout. The disease duration positively correlates with the development of pancreatic burnout. The liver seems to be more vulnerable to alcohol than the pancreas.

BACKGROUND: Alcohol abuse, a main cause of pancreatitis, has been known to augment NF-κB activation and cell necrosis in pancreatitis. However, the underlying mechanisms are unclear. We recently reported that inhibition of protein kinase D (PKD) alleviated NF- κB activation and severity of experimental pancreatitis. Here we investigated whether PKD signaling mediated the modulatory effects of alcohol abuse on pathological responses in alcoholic pancreatitis. METHODS: Alcoholic pancreatitis was provoked in two rodent models with pair-feeding control and ethanol-containing Lieber-DeCarli diets for up to 8 weeks followed by up to 7 hourly intraperitoneal injections of cerulein at 1μg/kg (rats) or 3μg/kg (mice). Effects of PKD inhibition by PKD inhibitors or genetic deletion of pancreatic PKD isoform (PKD3Δpanc mice) on alcoholic pancreatitis parameters were determined. RESULTS: Ethanol administration amplified PKD signaling by promoting expression and activation of pancreatic PKD, resulted in augmented/promoted pancreatitis responses. Pharmacological inhibition of PKD or with PKD3Δpanc mice prevented the augmenting/sensitizing effect of ethanol on NF-κB activation and inflammatory responses, cell necrotic death and the severity of disease in alcoholic pancreatitis. PKD inhibition prevented alcohol-enhanced trypsinogen activation, mRNA expression of multiple inflammatory molecules, the receptor-interacting protein kinase activation, ATP depletion, and downregulation of pro-survival Bcl-2 protein in alcoholic pancreatitis. Furthermore, PKD inhibitor CID755673 or CRT0066101, administrated after the induction of pancreatitis in mouse and rat alcoholic pancreatitis models, significantly mitigated the severity of pancreatitis. CONCLUSION: PKD mediates effect of alcohol abuse on pathological process of pancreatitis and constitutes a novel therapeutic target to treat this disease.

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.

Acute pancreatitis is an unpredictable and potentially lethal disease. The prognosis mainly depends on the development of organ failure and secondary infection of pancreatic or peripancreatic necrosis. In the past 10 years, treatment of acute pancreatitis has moved towards a multidisciplinary, tailored, and minimally invasive approach. Despite improvements in treatment and critical care, severe acute pancreatitis is still associated with high mortality rates. In this Seminar, we outline the latest evidence on diagnostic and therapeutic strategies for acute pancreatitis.

IgG4-related disease (IgG4-RD) is a systemic inflammatory disease, which includes type 1 autoimmune pancreatitis (AIP). Interleukin-35 (IL-35) exhibits immunosuppressive effects in several autoimmune diseases. However, the expression of IL-35 had not been reported so far in type 1 AIP. We evaluated the association between IL-35 and several cytokines, which mediate the function of Tregs in type 1 AIP. Plasma was collected from patients with type 1 AIP, alcoholic chronic pancreatitis (ACP), and healthy controls (HC) and assayed for cytokine expression. Total mRNA separated from peripheral blood was isolated from naive Tregs (nTregs) and effector Tregs (eTregs). EBI3 and IL-12p35 gene expressions were tested in these cells by quantitative PCR. In addition, expression of IL-35 subunits in the pancreatic tissues of patients with type 1 AIP and ACP was analyzed by immunohistochemistry. IL-35 was significantly elevated in type 1 AIP (n = 32) plasma compared with ACP (n = 16) and HC (n = 22), but IL-27 was not. We also detected many cells expressing both EBI3 and IL-12p35 in type 1 AIP tissues. Moreover, in peripheral blood lymphocyte, the percentage of nTregs and eTregs of CD4+ T cells in patients with type 1 AIP (n = 14) compared with HC (n = 15) was significantly decreased and increased, respectively. There were no significant differences of gene expression in patients with type 1 AIP and HC. This study identified elevated expression of plasma IL-35 and tissue IL-35 subunits in patients with type 1 AIP. This might lead to inflammation suppression via activated eTregs. IL-35 might be associated with this anti-inflammatory role, especially against the Th2 response through several cytokines and the differentiation of Tregs in type 1 AIP.

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.

Alcohol is a major cause of acute and chronic pancreatitis. There have been some recent advances in the understanding of the mechanisms underlying alcoholic pancreatitis, which include perturbation in mitochondrial function and autophagy and ectopic exocytosis, with some of these cellular events involving membrane fusion soluble N-ethylmaleimide-sensitive factor receptor protein receptor proteins. Although new insights have been unraveled recently, the precise mechanisms remain complex, and their finer details have yet to be established. The overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also the stellate cells and duct cells. Why only some are more susceptible to pancreatitis and with increased severity, while others are not, would suggest that there may be undefined protective factors or mechanisms that enhance recovery and regeneration after injury. Furthermore, there are confounding influences of lifestyle factors such as smoking and diet, and genetic background. Whereas alcohol and smoking cessation and a generally healthy lifestyle are intuitively the advice given to these patients afflicted with alcoholic pancreatitis in order to reduce disease recurrence and progression, there is as yet no specific treatment. A more complete understanding of the pathogenesis of pancreatitis from which novel therapeutic targets could be identified will have a great impact, particularly with the stubbornly high fatality (>30%) of severe pancreatitis. This review focuses on the susceptibility factors and underlying cellular mechanisms of alcohol injury on the exocrine pancreas.

The digestive protease chymotrypsin C (CTRC) protects the pancreas against pancreatitis by degrading potentially harmful trypsinogen. Loss-of-function genetic variants in CTRC increase risk for chronic pancreatitis (CP) with variable effect size, as judged by the reported odds ratio (OR) values. Here, we performed a meta-analysis of published studies on four variants that alter the CTRC amino-acid sequence, are clinically relatively common (global carrier frequency in CP >1%), reproducibly showed association with CP and their loss of function phenotype was verified experimentally. We found strong enrichment of CTRC variants p.A73T, p.V235I, p.K247_R254del, and p.R245W in CP cases versus controls, yielding OR values of 6.5 (95% confidence interval (CI) 2.4–17.8), 4.5 (CI 2.2–9.1), 5.4 (CI 2.6–11.0), and 2.6 (CI 1.6–4.2), respectively. Subgroup analysis demonstrated disease association of variants p.K247_R254del and p.R245W in alcoholic CP with similar effect sizes as seen in the overall CP group. Homozygosity or compound heterozygosity were rare and seemed to be associated with higher risk. We also identified a so far unreported linkage disequilibrium between variant p.K247_R254del and the common c.180C>T (p.G60 =) haplotype. Taken together, the results indicate that heterozygous loss-of-function CTRC variants increase the risk for CP approximately 3-7-fold. This meta-analysis confirms the clinical significance of CTRC variants and provides further justification for the genetic screening of CP patients.

Background Little information is available regarding the expression of the immunomodulatory Human Leukocyte Antigen (HLA)-G and -E molecules in pancreatic disorders. Aim To analyze HLA-G and -E expression in specimens of alcoholic chronic pancreatitis (ACP), idiopathic chronic pancreatitis (ICP), type 1 (T1D) and type 2 diabetes (T2D) and in histologically normal pancreas (HNP). Methods HLA-G and -E expression (ACP = 30, ICP = 10, T1D = 10, T2D = 30 and HNP = 20) was evaluated by immunohistochemistry in three different areas (acini, islets and inflammatory infiltrate). Results Acini and islets from HNP specimens exhibited higher HLA-G and -E expression compared to corresponding areas from all other patient groups. In inflammatory infiltrate, HLA-G and -E expression was observed only among the pancreatic disorders. We observed higher HLA-G and -E expression in acini from T2D compared to ACP, as well as higher HLA-G expression compared to ICP. Conclusion The decreased expression of HLA-G and -E in islets and acini together with the expression of these molecules in the inflammatory infiltrating cells were shared features among chronic inflammatory and autoimmune pancreatic disorders evaluated in this study, possibly reflecting tissue damage.

BACKGROUND AND AIMS: Heavy alcohol consumption is a common cause of acute pancreatitis, however, alcohol abuse does not always result in clinical pancreatitis. As a consequence, the factors responsible for alcohol-induced pancreatitis are not well understood. In experimental animals it has been difficult to produce pancreatitis with alcohol. Clinically, alcohol use predisposes to hypophosphatemia and hypophosphatemia has been observed in some patients with acute pancreatitis. Due to abundant protein synthesis, the pancreas has high metabolic demands, and reduced mitochondrial function leads to organelle dysfunction and pancreatitis. We proposed, therefore, that phosphate deficiency might limit ATP synthesis and, thereby, contribute to alcohol-induced pancreatitis. METHODS: Mice were fed a low phosphate diet (LPD) prior to orogastric administration of ethanol. Direct effects of phosphate and ethanol were evaluated in vitro in isolated mouse pancreatic acini. RESULTS: LPD reduced serum phosphate levels. Intragastric administration of ethanol to animals maintained on a LPD caused severe pancreatitis that was ameliorated by phosphate repletion. In pancreatic acinar cells, low phosphate conditions increased susceptibility to ethanol-induced cellular dysfunction through decreased bioenergetic stores, specifically affecting total cellular ATP and mitochondrial function. Phosphate supplementation prevented ethanol-associated cellular injury. CONCLUSION: Phosphate status plays a critical role in predisposition to and protection from alcohol-induced acinar cell dysfunction and the development of acute alcohol-induced pancreatitis. This finding may explain why pancreatitis develops in only some individuals with heavy alcohol use and suggests a potential novel therapeutic approach to pancreatitis. Finally, low phosphate diet + ethanol provides a new model for studying alcohol-associated pancreatic injury.

Reports of pulmonary embolism in the setting of acute pancreatitis are rare. We present three cases of acute pancreatitis associated with pulmonary embolism and review the literature. Two of the three patients had severe acute pancreatitis with bilateral pulmonary emboli, and to our knowledge, these cases represent the first report of pulmonary embolism occurring in the setting of pancreatic ascites and pleural effusion. All patients experienced abdominal pain, though in one patient, symptoms suggestive of a pulmonary embolism were lacking. All three patients were successfully treated with unfractionated heparin and conservative management. Pulmonary thrombosis may occur in the setting of severe acute pancreatitis as the result of systemic inflammatory response. We review the literature and provide microvascular explanations for the occurrence of pulmonary complications and thrombosis in the setting of acute pancreatitis. We also review prior cases of pulmonary embolism in acute pancreatitis. Our experience suggests that pulmonary embolism may be an under-recognized complication of severe acute pancreatitis.

Modified Marshall Score is one of the severity scores for acute pancreatitis (AP) and is included in the Revised Atlanta Classification, but given its utilization of a set serum creatinine level (sCr), it may misclassify stable patients with chronic kidney disease (CKD) to a more severe class just due to their elevated sCr. Our study aims to evaluate the role of CKD in AP and the possibility of utilizing acute kidney injury (AKI) into developing a new scoring system. We retrospectively reviewed the electronic medical records of three hundred consecutive patients who were diagnosed with AP during hospitalization. Multiple demographic variables and clinical course indices were collected. Univariate logistic regression was then applied to predict mortality and ICU admission. Finally, receiver operating curve was utilized to compare original versus New Revised Marshall Score. Two hundred and eight-four (284) patients had a definitive diagnosis of AP. When comparing patients who had AKI on admission to those without AKI, the AKI group showed statistically significant higher mortality rate (5.6% vs. 1.1%, p = 0.04). Finally, we substituted the renal part of Marshall Score with our AKIN and we plotted the New “Revised” Marshall Score, which showed a higher AUROC compared to the original modified version (C-statistics 0.93 vs. 0.89, p

The diagnosis of severe hypertriglyceridemia (HTG) as a cause for acute pancreatitis is often delayed with limited data on the characteristics and predictors of recurrent pancreatitis in this population.A regional database of severe HTG level of 1000 mg/dL or greater was analyzed to identify subjects with acute pancreatitis. Factors associated with recurrent pancreatitis during long-term follow-up were investigated.Severe HTG-associated pancreatitis was evident in 171 patients (75% diabetics). Recurrent pancreatitis was observed in 16%; this was associated with younger age, alcohol abuse, and an increase in triglyceride levels. In multivariable analysis, peak triglycerides level of greater than 3000 mg/dL (hazard ratio, 2.92; 95% confidence interval, 1.28-6.64; P = 0.011) and most recent triglycerides level of greater than 500 mg/dL (hazard ratio, 3.72; 95% confidence interval, 1.60-8.66; P = 0.002) remained independently associated with recurrent pancreatitis. These lipid measures as well as alcohol abuse were additionally correlated with a stepwise increase in the number of pancreatitis episodes.Severe HTG-related pancreatitis was closely associated with diabetes. Extreme HTG and a lack of attainment of lower triglyceride levels were independent long-term predictors of recurrent pancreatitis. These findings emphasize the importance of early identification and successful treatment of severe HTG and its underlying disorders to reduce the burden of recurrent pancreatitis.

Background Recurrent pain is the most disabling complication in patients with chronic pancreatitis. Pancreatic surgery is currently considered as last-resort therapeutic option. The aims of this study were to assess pancreatic surgery performance for chronic pain in patients with alcoholic chronic pancreatitis and to determine factors predictive of therapeutic response. Methods All patients with chronic pancreatitis who underwent pancreatic surgery for chronic pain were included and divided into 2 groups according to the cause of chronic pancreatitis: alcoholic and any other chronic pancreatitis causes as the control group. Alcohol, tobacco, and painkiller intake, quality of life data 6 months and 1 year after surgery, and morphological and pathological features were analyzed. Results Fifty patients were included in the alcoholic chronic pancreatitis group and 16 patients in the control group. Smoking cessation before pancreatic surgery was achieved in 40% of the alcoholic chronic pancreatitis group compared with 73% of the control group (P = .005). Histological analysis revealed a higher prevalence of hypertrophic nerves and perineural inflammation in the alcoholic chronic pancreatitis group than in the control group (P = .03 and P = .04 respectively). In multivariate analysis, in the alcoholic chronic pancreatitis group, factors predictive of 6-month narcotic use cessation were surgery performed within a maximum of 2 years after chronic pancreatitis diagnosis (odds ratio = 4.228 [1.04–17.17]) and postoperative smoking cessation (odds ratio = 3.561 [1.021–12.41]); at 1 year, only smoking cessation was predictive of narcotic use cessation (odds ratio = 11.33 [2.677–47.98]). Conclusion In patients with alcoholic chronic pancreatitis undergoing surgery for chronic pain, narcotic use cessation and improved quality of life depend on early surgery and complete smoking cessation.

Background/Objectives Alcohol is the most common etiology of recurrent acute pancreatitis and chronic pancreatitis. The extent and timing of drinking that increases the transient risk of acute pancreatitis is yet unknown. Methods We designed a case-crossover study to determine the effective hazard period of drinking in relation to episodes of pancreatitis. We aim to evaluate the dose-response relationship between excess drinking and pancreatitis comparing the extent of drinking during case and control periods from the same individual. We aim to recruit 160 patients hospitalized with acute pancreatitis, whose AUDIT-C score reaches 3 or higher. Interviews of each enrolled patient to define their 15-day history of alcohol consumption employing the timeline follow-back method. Long-term drinking and smoking will be investigated as modifiers of the impact of short-term excess drinking. Patients are followed-up for evaluation of usual alcohol consumption during asymptomatic periods following the index hospitalization. Blood and urine specimens are collected while the patients are hospitalized and during a standard-of-care follow-up visit. Results We have recruited 31 patients to date, with a median age of 33 years. Females and non-White participants make up 26% and 35% of the enrolled population, respectively. Forty-eight % of patients have had a prior history of acute pancreatitis. Conclusions Our study will shed light on the impact of short-term changes in drinking on triggering acute pancreatitis. It will provide data on other covarying factors of drinking and behaviors changes after acute pancreatitis.

INTRODUCTION: Although coexistence of alcohol-related liver disease (ALD) and pancreatitis (ALP) is seen in clinical practice, a clear understanding of the overlap between these diseases is lacking. Moreover, the relative risks for certain population groups have not been studied. We determined the prevalence and coexistence of ALD and ALP in patients with an alcohol use disorder using retrospective analysis of a large patient cohort from Western Pennsylvania. We specifically emphasized the analysis of underrepresented populations, including women and blacks. METHODS: We identified all unique patients who received care in UPMC health system during 2006–2017 with at least one International Classification of Diseases versions 9 and/or 10 codes for alcohol misuse, ALD and pancreatitis. We noted their sex, race and age of first diagnosis and duration of contact. RESULTS: Among 89,774 patients that fit our criteria, the prevalence of ALD, ALP and coexistent ALD and ALP in patients with alcohol misuse was 11.7%, 7.4% and 2.5%, respectively. Prevalence of ALP in ALD was 16.4%, and ALD in ALP was 33.1%. Prevalence of ALP in ALD was slightly more prevalent in women (18.6% vs. 15.6%, p < 0.001). Prevalence of ALP in ALD was 2–4 folds greater in blacks than other races. DISCUSSION: A sizeable fraction of patients with ALD or ALP has coexistent disease. This is the first study to identify that blacks are at a higher risk for ALP in the presence of ALD. Future studies should define the clinical impact of coexistent disease on clinical presentation and short- and long-term outcomes.

Chronic, heavy alcohol consumption disrupts normal organ function and causes structural damage in virtually every tissue of the body. Current diagnostic terminology states that a person who drinks alcohol excessively has alcohol use disorder. The liver is especially susceptible to alcohol-induced damage. This review summarizes and describes the effects of chronic alcohol use not only on the liver, but also on other selected organs and systems affected by continual heavy drinking—including the gastrointestinal tract, pancreas, heart, and bone. Most significantly, the recovery process after cessation of alcohol consumption (abstinence) is explored. Depending on the organ and whether there is relapse, functional recovery is possible. Even after years of heavy alcohol use, the liver has a remarkable regenerative capacity and, following alcohol removal, can recover a significant portion of its original mass and function. Other organs show recovery after abstinence as well. Data on studies of both heavy alcohol use among humans and animal models of chronic ethanol feeding are discussed. This review describes how (or whether) each organ/tissue metabolizes ethanol, as metabolism influences the organ’s degree of injury. Damage sustained by the organ/tissue is reviewed, and evidence for recovery during abstinence is presented.

Chronic pancreatitis (CP) is a risk factor for developing pancreatic ductal adenocarcinoma (PDAC). In addition, a patient with partial pancreatectomy for intraductal papillary mucinous neoplasm (IPMN) can also lead to PDAC. In contrast, IPMN is a distinct disease entity, independent of CP, and there have been few reports that CP is the cause of IPMN. To the best of our knowledge, this is the first clinical case report of the metachronous occurrence of main-duct IPMN and PDAC with a 9 and half-year interval in a patient with chronic alcoholic pancreatitis.A 50-year-old man with a long medical history of recurrent alcoholic pancreatitis and hepatitis over a decade was diagnosed with another episode of acute pancreatitis based on laboratory findings and clinical symptoms. The patient underwent pylorus-preserving pancreaticoduodenectomy (PPPD) for a small nodular lesion in the main duct of the pancreatic head and was diagnosed with main-duct IPMN low-grade dysplasia and associated fibrosing CP. Nine and a half years later, a 59-year-old man lost 7 kg over 3 months and was diagnosed with new-onset diabetes mellitus.The patient was diagnosed with metachronous, well-differentiated PDAC with concomitant CP.The patient underwent radical antegrade modular pancreatosplenectomy (RAMPS) for a small nodular mass in the remnant pancreas.The patient was healthy for 44 months without evidence of tumor recurrence during clinical follow-up examinations including laboratory findings, tumor marker, and imaging studies.Early diagnosis of metachronous pancreatic neoplasia in a patient with chronic pancreatitis could be made by correlating newly developed clinical symptoms and signs with careful radiological examinations.

Inflammatory bowel disease (IBD) can involve multiple organ systems, and pancreatic manifestations of IBD are not uncommon. The incidence of several pancreatic diseases is more frequent in patients with Crohn's disease and ulcerative colitis than in the general population. Pancreatic manifestations in IBD include a heterogeneous group of disorders and abnormalities ranging from mild, self-limited disorders to severe diseases. Asymptomatic elevation of amylase and/or lipase is common. The risk of acute pancreatitis in patients with IBD is increased due to the higher incidence of cholelithiasis and drug-induced pancreatitis in this population. Patients with IBD commonly have altered pancreatic histology and chronic pancreatic exocrine dysfunction. Diagnosing acute pancreatitis in patients with IBD is challenging. In this review, we discuss the manifestations and possible causes of pancreatic abnormalities in patients with IBD.

The association between a common PRSS1-PRSS2 haplotype and alcoholic chronic pancreatitis (ACP), which was revealed by the first genome-wide association study of chronic pancreatitis (CP), has been consistently replicated. However, the association with non-ACP (NACP) has been controversial. Herein, we sought to clarify this basic issue by means of an allele-based meta-analysis of currently available studies. We then used studies informative for genotype distribution to explore the biological mechanisms underlying the association data and to test for gene-environment interaction between the risk haplotype and alcohol consumption by means of a re-analysis. A literature search was conducted to identify eligible studies. A meta-analysis was performed using the Review Manager software. The association between the risk genotypes and NACP or ACP was tested for the best-fitting genetic model. Gene-environment interaction was estimated by both case-only and multinomial approaches. Five and eight studies were employed for the meta-analysis of ACP and NACP findings, respectively. The risk allele was significantly associated with both ACP (pooled odds ratio (OR) 1.67, 95% confidence interval (CI) 1.56&ndash, 1.78, p &lt, 0.00001) and NACP (pooled OR 1.28, 95% CI 1.17&ndash, 1.40, 0.00001). Consistent with a dosage effect of the risk allele on PRSS1/PRSS2 mRNA expression in human pancreatic tissue, both ACP and NACP association data were best explained by an additive genetic model. Finally, the risk haplotype was found to interact synergistically with alcohol consumption.

Chronic pancreatitis (CP) is a risk factor for pancreatic ductal adenocarcinoma (PDAC); nevertheless, the true incidence of PDAC in CP patients in the United States remains unclear.We evaluated the risk of developing PDAC two or more years after a new diagnosis of CP.Retrospective study of veterans from September 1999 to October 2015. A three-year washout period was applied to exclude patients with preexisting CP and PDAC. PDAC risk was evaluated in patients with new-diagnosis CP and compared with controls without CP using Cox-proportional hazards model. CP, PDAC, and other covariates were extracted using ICD-9 codes.After exclusions, we identified 7,883,893 patients [new-diagnosis CP - 21,765 (0.28%)]. PDAC was diagnosed in 226 (1.04%) patients in the CP group and 15,858 (0.20%) patients in the control group (p 0.001). CP patients had a significantly higher PDAC risk compared to controls 2 years [adjusted hazard ratio (HR) 4.28, 95% confidence interval (CI) 3.74-4.89, p 0.001], 5 years (adjusted HR 3.32, 95% CI 2.75-4.00, p 0.001) and 10 years of follow-up (adjusted HR 3.14, 95% CI 1.99-4.93, p 0.001), respectively. By multivariable analysis, age (odds ratio 1.02, 95% CI 1.00-1.03, p = 0.03), current smoker (odds ratio 1.67, 95% CI 1.02-2.74, p = 0.042), current smoker + alcoholic (odds ratio 2.29, 95% CI 1.41-3.52, p 0.001), and diabetes (odds ratio 1.51, 95% CI 1.14-1.99, p = 0.004) were the independent risk factors for PDAC.Our data show that after controlling for etiology of CP and other cofactors, the risk of PDAC increased in CP patients after two years of follow-up, and risk was consistent and sustained beyond 5 years and 10 years of follow-up.

Gastrointestinal fistulization (GIF) is a rare and potentially fatal complication of acute necrotizing pancreatitis (ANP). There is paucity of data on clinical course and outcome of GIF in walled of necrosis (WON). To evaluate frequency, clinical as well as imaging findings and outcome of spontaneous symptomatic GIF in patients with WON. Retrospective analysis of database of patients with asymptomatic WON on regular follow-up over last six years to identify patients with symptomatic GIF. Out of 138 patients with asymptomatic WON seen during the study period, 16 (11.5%) patients (all males; mean age 41.7 ± 9.9 years) developed symptomatic GIF. The mean size of WON in patients who developed GIF was 9.5 ± 2.4 cm, and fistulization occurred after 65.1 ± 17.8 days of the onset of ANP. The site of fistulization was stomach, duodenum, jejunum, colon, and esophagus in seven (43.7%), five (31.2%), one (6.2%), two (12.5%), and one (6.2%) patients, respectively. GIF resulted in spontaneous resolution in two patients (stomach 1 and esophagus 1). The remaining patients with gastric (six patients) and duodenal (five patients) fistulization were successfully treated endoscopically by placing multiple plastic stents in the necrotic cavity after balloon dilatation of the fistulous tract. Patients with colonic fistulization required surgery. None of the patients succumbed to the illness. Symptomatic GIF of WON usually occurs within the first three months of onset of ANP. It commonly occurs in either stomach or duodenum and can be successfully managed endoscopically.

Toxicological analysis is an important diagnostic component of a postmortem examination and may involve both antemortem and postmortem specimens. Here, we present a case in which an antemortem specimen, when reanalyzed in the forensic toxicology laboratory, resulted in values that contradicted the reported values from the medical record and required further investigation. This case involves a 51-year-old man decedent with a medical history of chronic alcohol abuse. His antemortem urine drug screen, performed upon admission to an emergency department, was negative. His serum blood alcohol level at presentation was reported as 0.960 g/dL and, repeated 4 hours later, was 0.500 g/dL with a comment indicating that there was significant lipemia interfering with the results. At autopsy, the antemortem blood sample collected from the hospital, postmortem blood, and vitreous humor samples were analyzed and all 3 samples were found to be negative for ethanol. The hospital laboratory used an enzymatic assay for ethanol detection, which is known to be impacted by lipemia, and the forensic laboratory used head-space gas chromatography, which is not impacted by lipemia. This highlights the need to critically analyze laboratory testing methodologies when interpreting conflicting results at autopsy.

Alcohol consumption is always the main cause of acute pancreatitis (AP). It has been reported that alcohol exerts direct damage to the pancreas. However, the specific role of alcohol during AP needs to be investigated. This study aims to examine the effects of alcohol in cerulein-induced AP and the role of the AMPK pathway. Human subjects from operations, cerulein-induced AP rat, and cerulein-stimulated AR42J cell line were enrolled in this study. Electron microscopy was employed for observation of cell morphology, immunohistochemistry for identification of cells, ELISA for detection of inflammation factors, Annexin V/PI double staining for evaluation of cell apoptosis, immunofluorescence for assessment of autophagic flux, oil red O staining for examination of lipid droplet accumulation, and Western blot for measurement of expressions of proteins related to autophagy, apoptosis, and AMPK signal pathway. PI3K inhibitor 3-MA and AMPK inhibitor BML-275 were utilized for investigation of the relationship between impaired autophagic flux and the AMPK pathway by inhibiting or stimulating the formation of autophagosome. Alcohol consumption caused lipid droplet accumulation in the pancreas, and it also activated AMPK signaling pathway, thus aggravating the autophagic flux during AP. Alcohol up-regulated the expressions of anti-apoptotic proteins during the induction of AP to inhibit cell apoptosis and enhance cell necrosis. Inhibition of autophagosome formation by AMPK inhibitor BML-275 ameliorated the decreased cell viability caused by alcohol and cerulein in vitro. Alcohol aggravates AP progression by impairing autophagic flux and enhancing cell autophagy through the AMPK signaling pathway.

Alcoholic acute pancreatitis (AAP) comprises the second most common cause of acute pancreatitis in the USA, and there is lack of data regarding 30-day specific readmission causes and predictors. We aim to identify 30-day readmission rate, causes, and predictors of readmission.Retrospective analysis of the 2016 National Readmission Database of adult patients readmitted within 30 days after an index admission for AAP.Totally, 76,609 AAP patients were discharged from the hospital in 2016. The 30-day readmission rate was 12%. The main cause of readmission was another episode of AAP. Readmission was not associated with higher mortality (1.3% vs. 1.2%; P = 0.21) or prolonged length of stay (5.2 vs. 5.0 days; P = 0.06). The total health care economic burden was $354 million in charges and $90 million in costs. Independent predictors of readmission were having Medicaid insurance, a Charlson comorbidity index score ≥ 3, use of total parenteral nutrition, opioid abuse disorder, prior pancreatic cyst, chronic alcoholic pancreatitis, and other chronic pancreatitis. Obesity was associated with lower odds of readmission.Readmission rate for AAP is high and its primary cause are recurrent episodes of AAP. Alcohol and substance abuse pose a high burden on our health care system. Public health strategies should be targeted to provide alcohol abuse disorder rehabilitation and cessation resources to alleviate the burden on readmission, the health care system and to improve patient outcomes.

Background Available estimates of coexistent alcohol-related pancreatitis (ALP) and alcohol-related liver disease (ALD) vary widely, and factors that determine coexistent disease are largely unknown. We performed a systematic review of published literature with the primary aim to generate robust estimates for coexistent alcohol-related chronic pancreatitis (ACP) and alcohol-related cirrhosis (ALC). Methods We searched PubMed, EMBASE, and Web of Science databases from inception until February 2018. Studies included were those in English-language, sample size ≥25 and allowed calculation of the coexistent disease. Pooled estimates were calculated using a random-effects model approach. Results Twenty-nine (including 5 autopsy studies) of 2000 eligible studies met inclusion criteria. Only 6.9% included patients were female. Fifteen studies enabled calculation of ACP in ALC, and 11 for ALC in ACP. Pooled prevalence of ACP in ALC was 16.2% (95% CI 10.4–24.5) overall, and 15.5% (95% CI 8.0–27.7) when data were limited to clinical studies. Corresponding prevalence for ALC in ACP was 21.5% (95% CI 12.0–35.6) and 16.9% (95% CI 11.5–24.3), respectively. There was significant heterogeneity among studies (I2 – 65–92%). Pooled prevalence for ALP in ALD or ALD in ALP in clinical studies were 15.2% and 39%, respectively. None of the studies reported outcomes in patients with coexistent disease. Conclusion A sizeable fraction of patients with ACP or ALC have coexistent disease. Future studies should define the prevalence of coexistent disease in women and minority populations, and the consequences of coexistent disease on clinical presentation and short- and long-term outcomes.

Vascular complications such as venous thrombosis (VT) and pseudoaneurysm are not uncommon in patients with chronic pancreatitis (CP). The aim of this study to was to evaluate the prevalence and risk factors for vascular complications in patients with CP.A retrospective analysis of a prospectively maintained database of patients with CP presenting from January 2002 to August 2019 was performed. Venous thrombosis and pseudoaneurysm were identified using radiological imaging, and their risk factors were identified using multivariate Cox-proportional hazards.Of 1363 patients with CP, 166 (12.2%) had vascular complications. Isolated VT was present in 132, pseudoaneurysm in 17, and both in 17 patients. They were more commonly seen in males and alcoholic CP (ACP), and less commonly in patients with pancreatic atrophy and calcification. It involved the vessels in the closest proximity to the pancreas, VT most commonly involving the splenic vein whereas pseudoaneurysm most commonly involved the splenic artery. Alcoholic CP [odds ratio (OR) 2.1, p = 0.002], pseudocyst (OR 4.6, p 0.001) and inflammatory head mass (OR 3.1, p = 0.006) were independent risk factors for VT, whereas ACP (OR 3.49, p = 0.006) and pseudocyst (OR 3.2, p = 0.002) were independent risk factors for pseudoaneurysm. Gastrointestinal bleed occurred in 3.5% patients, and more commonly in patients with pseudoaneurysm than VT (64.7% vs 15.9%), and in patients with ACP in comparison to other etiologies (p 0.001).Vascular complications are a common complication of CP, VT being more frequent than pseudoaneurysm. Pseudocyst and ACP are independent risk factors for the development of vascular complications.

Severe acute alcoholic pancreatitis is a second common form of pancreatitis that requires intensive care unit care and has high morbidity and mortality due to lacking specific treatment. Management of alcoholic pancreatitis is generally non- specific and supportive. We hereby present a case-series of three patients that describes the successful treatment of severe acute alcoholic pancreatitis with ulinastatin and other supportive treatment. From this we want to emphasize that ulinastatin a protease inhibitor can be used in the treatment of alcoholic pancreatitis.

Alcoholic pancreatitis is a multifactorial, progressive, inflammatory disorder of the pancreas. Alcohol initiates pancreatitis and promotes its progression in the context of genetic susceptibility and/or other environmental risk factors such as smoking. Genetic mutations can cause digestive enzyme misfolding, which induces endoplasmic reticulum (ER) stress and elicits pancreatitis. Here, we tested the hypothesis that alcohol synergizes with misfolding in promoting ER stress and thereby accelerates chronic pancreatitis progression. To this end, we fed an ethanol-containing diet to CPA1 N256K mice, which carry the human p.N256K CPA1 mutation and develop spontaneous chronic pancreatitis. Inexplicably, CPA1 N256K mice suffered generalized seizures after 2–3 wk of ethanol feeding, which resulted in high mortality and the early termination of the study. Analysis of CPA1 N256K mice euthanized after 3–3.5 wk of ethanol feeding revealed more severe chronic pancreatitis associated with significantly increased Hspa5 [ER chaperone immunoglobulin heavy chain-binding protein (BiP)] mRNA levels when compared with CPA1 N256K mice on a control liquid diet. In contrast, ethanol feeding of C57BL/6N mice for 4 wk increased Hspa5 levels to a lesser degree and caused no pancreatitis. We conclude that ethanol feeding synergizes with the misfolding CPA1 mutant in promoting ER stress and thereby accelerates progression of chronic pancreatitis in CPA1 N256K mice. NEW & NOTEWORTHY Alcoholic pancreatitis is a multifactorial, progressive, inflammatory disorder of the pancreas. This study demonstrates that alcohol synergizes with digestive enzyme misfolding in promoting endoplasmic reticulum stress and thereby accelerates progression of chronic pancreatitis.

Background/objectives Carboxyl ester lipase is a pancreatic enzyme encoded by CEL, an extremely polymorphic human gene. Pathogenic variants of CEL either increases the risk for chronic pancreatitis (CP) or cause MODY8, a syndrome of pancreatic exocrine and endocrine dysfunction. Here, we aimed to characterize a novel duplication allele of CEL (CEL-DUP2) and to investigate whether it associates with CP or pancreatic cancer. Methods The structure of CEL-DUP2 was determined by a combination of Sanger sequencing, DNA fragment analysis, multiplex ligation-dependent probe amplification and whole-genome sequencing. We developed assays for screening of CEL-DUP2 and analyzed cohorts of idiopathic CP, alcoholic CP and pancreatic cancer. CEL protein expression was analyzed by immunohistochemistry. Results CEL-DUP2 consists of an extra copy of the complete CEL gene. The allele has probably arisen from non-allelic, homologous recombination involving the adjacent pseudogene of CEL. We found no association between CEL-DUP2 carrier frequency and CP in cohorts from France (cases/controls: 2.5%/2.4%; P = 1.0), China (10.3%/8.1%; P = 0.08) or Germany (1.6%/2.3%; P = 0.62). Similarly, no association with disease was observed in alcohol-induced pancreatitis (Germany: 3.2%/2.3%; P = 0.51) or pancreatic cancer (Norway; 2.5%/3.2%; P = 0.77). Notably, the carrier frequency of CEL-DUP2 was more than three-fold higher in Chinese compared with Europeans. CEL protein expression was similar in tissues from CEL-DUP2 carriers and controls. Conclusions Our results support the contention that the number of CEL alleles does not influence the risk of pancreatic exocrine disease. Rather, the pathogenic CEL variants identified so far involve exon 11 sequence changes that substantially alter the protein’s tail region.

Background Genetic mutations are one of the etiological factors that predispose people to develop chronic pancreatitis. Objectives The aim of our study was to examine the effect of p.Trp55*, p.Arg254Trp and c.738_761del mutations in the chemotrypsin gene (CTRC) on the development of alcoholic chronic pancreatitis (ACP) in order to answer the questions whether these mutations vary between gender groups, whether they were related to the age when ACP was first diagnosed, and whether they affected the morphological changes in the pancreas and the course of ACP. Material and methods The study included 124 patients with ACP, 52 with nonalcoholic pancreatitis and 52 controls. The p.Trp55*, c.738_761del and p.Arg254Trp mutations in the CTRC gene were tested by the polymerase chain reaction (PCR). Results The c.738_761del and p.Arg254Trp mutations occurred in 3.07% and 1.31% of cases, respectively. None of the examined patients were found to have the p.Trp55* mutation. The frequency of detected mutations did not significantly differ between the study groups. The c.738_761del mutation was detected more frequently in women than in men. No significant differences were found in the age at ACP onset, morphological changes affecting the pancreas, or in the course of ACP between the patients with and without the 2 examined mutations. The c.738_761del mutation was significantly more frequent in the diabetic patients than in the non-diabetics. The patients with this mutation more frequently required surgery than those without the c.738_761del mutation. Conclusions No relationship between the c.738_761del and p.Arg254Trp mutations and the development of APC was found. The c.738_761del mutation was more frequent in females than in males. Neither mutation affected the patient's age at ACP onset or its course. In contrast to p.Arg254Trp, the c.738_761del mutation correlated with diabetes development and the need for surgery in the course of ACP.

Background /Objectives: Severe acute pancreatitis (SAP) has a high mortality rate despite ongoing attempts to improve prognosis through a various therapeutic modalities. This study aimed to delineate etiology-based routes that may guide clinical decisions for the treatment of SAP. Methods Using data from a recent retrospective multicenter study in Japan, we analyzed the association between clinical outcomes, mainly in-hospital mortality and pancreatic infection, and various etiologies while considering confounding factors. We performed additional multivariate analyses and built decision tree models. Results The 1,097 participating patients were classified into the following groups by etiology: alcohol (n = 436, 39.7%); cholelithiasis (n = 230, 21.0%); idiopathic (n = 227, 20.7%); and others (n = 204, 18.6%). Mortality at hospital discharge was 8.4%, 12.2%, 16.7%, and 16.2% in the alcohol, cholelithiasis, idiopathic, and others groups, respectively. According to multivariable analysis, early enteral nutrition (EN) was significantly associated with reduced in-hospital mortality only in the cholelithiasis group. However, there was a consistent association between age and the need for mechanical ventilation and increased mortality, regardless of etiology. Our decision tree models presented different contributing factors depending on the etiology and patient background. Interaction analysis showed that EN and the use of prophylactic antibiotics may influence these results differently according to etiology. Conclusions No study has yet used comprehensive models to investigate etiology-related prognostic factors for SAP; our results can, therefore, be used as a reference for improving clinical decisions.

Acute pancreatitis (AP) is a severe disease associated with significant morbidity and mortality. The overall outcome has improved, but specific treatment(s) remains elusive. The challenge is the early identification and treatment of patients who will develop severe acute pancreatitis. Therefore, the aim of the present study is to investigate plasma levels of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in the initial phase of predicted severe acute pancreatitis. Between June 2014 and January 2016, 64 patients with acute pancreatitis and 36 healthy individuals were included to study. Four blood samples, for serum TWEAK measurement, were taken from each individual in each group. The first measurement was taken from the admission blood sample. The subsequent three samples were taken at 12, 24, and 48 h after the hospital admission. Serum TWEAK levels were significantly higher in patients with acute pancreatitis when compared with healthy controls. TWEAK plasma concentrations in severe pancreatitis patients were significantly higher than in mild pancreatitis patients. Serum TWEAK levels increase progressively with the severity of acute pancreatitis and TWEAK might be a novel early marker of severity in acute pancreatitis.

Pancreatic stellate cells (PSCs) play a critical role in fibrogenesis during alcoholic chronic pancreatitis (ACP). Transforming growth factor‐beta1 (TGF‐β1) is a key regulator of extracellular matrix production and PSC activation. Endotoxin lipopolysaccharide (LPS) has been recognized as a trigger factor in the pathogenesis of ACP. This study aimed to investigate the mechanisms by which LPS modulates TGF‐β1 signalling and pancreatic fibrosis. Sprague‐Dawley rats fed with a Lieber‐DeCarli alcohol (ALC) liquid diet for 10 weeks with or without LPS challenge during the last 3 weeks. In vitro studies were performed using rat macrophages (Mφs) and PSCs (RP‐2 cell line). The results showed that repeated LPS challenge resulted in significantly more collagen production and PSC activation compared to rats fed with ALC alone. LPS administration caused overexpression of pancreatic TLR4 or TGF‐β1 which was paralleled by an increased number of TLR4‐positive or TGF‐β1‐positive Mφs or PSCs in ALC‐fed rats. In vitro, TLR4 or TGF‐β1 production in Mφs or RP‐2 cells was up‐regulated by LPS. LPS alone or in combination with TGF‐β1 significantly increased type I collagen and α‐SMA production and Smad2 and 3 phosphorylation in serum‐starved RP‐2 cells. TGF‐β pseudoreceptor BAMBI production was repressed by LPS, which was antagonized by Si‐TLR4 RNA or by inhibitors of MyD88/NF‐kB. Additionally, knockdown of Bambi with Si‐Bambi RNA significantly increased TGF‐β1 signalling in RP‐2 cells. These findings indicate that LPS increases TGF‐β1 production through paracrine and autocrine mechanisms and that LPS enhances TGF‐β1 signalling in PSCs by repressing BAMBI via TLR4/MyD88/NF‐kB activation.

Background Pancreatic fibrosis is a key pathological feature of alcoholic chronic pancreatitis (ACP). Bacterial endotoxin lipopolysaccharide (LPS) is considered as an important cofactor in the fibrogenesis of ACP. However, there are limitations in the use of exogenous LPS for evaluating the role of endotoxin in ACP pathogenesis. In this study, we determined the relationship between the concentration of LPS in the portal vein and pancreatic type I collagen (Col1) content in chronic alcohol-fed rats. Methods Male Sprague Dawley rats were divided into 2 groups and fed with Lieber–DeCarli isocaloric control (CON) liquid diet or ethanol (EtOH) (15 g/kg/d) liquid diet. Eleven CON or EtOH rats were euthanized at the end of week 8, 9, or 10. The plasma LPS from portal vein was determined. Pancreatic inflammatory injury and fibrosis were assessed. Pancreatic stellate cells (PSCs) and macrophages were identified; pancreatic type I collagen alpha 1 (Col1A1) and Toll-like receptor (TLR4) mRNA and protein were examined; pancreatic chemokines and transforming growth factor-beta1 (TGF-β1) were determined. Results Pancreatic inflammatory scores were increased in 10-week EtOH rats compared with CON rats, but there was no significant difference in collagen deposition between 2 groups. The levels of portal vein LPS and pancreatic TLR4 and Col1A1 mRNA and protein were increased in a time-dependent fashion in EtOH rats, with the highest levels occurring at 10 weeks. Additionally, by 8 weeks, pancreatic TLR4 and Col1A1 mRNA in EtOH rats were statistically increased as compared to CON rats, whereas portal vein LPS remained unchanged. The number of PSCs and macrophages and expression of chemokines (MCP-1, MIP-1α, and RANTES), TGF-β1, or Col1A1 were significantly increased, each of which was positively correlated with the level of portal vein LPS in 10-week EtOH rats. Conclusions These results suggest that LPS is associated with alcohol-induced fibrosis in pancreatitis and targeting of bacterial endotoxin may be a promising therapeutic strategy for ACP.

Acute pancreatitis is a fascinating disease. In the United States, the two most common etiologies of acute pancreatitis are gallstones and excessive alcohol consumption. The diagnosis of acute pancreatitis is made with a combination of history, physical examination, computed tomography scan, and laboratory evaluation. Differentiating patients who will have a benign course of their pancreatitis from patients who will have severe pancreatitis is challenging to the clinician. C-reactive protein, pro-calcitonin, and the Bedside Index for Severity of Acute Pancreatitis appeared to be the best tools for the early and accurate diagnosis of severe pancreatitis. Early laparoscopic cholecystectomy is indicated for patients with mild gallstone pancreatitis. For patients who are going to have a prolonged hospitalization, enteral nutrition is preferred. Total parenteral nutrition should be reserved for patients who cannot tolerate enteral nutrition. Prophylactic antibiotics are not indicated for patients with pancreatic necrosis. Surgical intervention for infected pancreatic necrosis should be delayed as long as possible to improve patient outcomes.

BACKGROUND Alcohol-related mortality is more pronounced in lower than in higher socioeconomic groups in Western countries. Part of the explanation is differences in drinking patterns. However, differences in vulnerability to health consequences of alcohol consumption across socioeconomic groups may also play a role. We investigated the joint effect of alcohol consumption and educational level on the rate of alcohol-related medical events. METHODS We pooled seven prospective cohorts from Denmark that enrolled 74,278 men and women age 30-70 years (study period, 1981 to 2009). We measured alcohol consumption at baseline using self-administrated questionnaires. Information on highest attained education 1 year before study entry and hospital and mortality data on alcohol-related medical events were obtained through linkage to nationwide registries. We performed analyses using the Aalen additive hazards model. RESULTS During follow-up (1,085,049 person-years), a total of 1718 alcohol-related events occurred. The joint effect of very high alcohol consumption (>21 [>28] drinks per week in women [men]) and low education on alcohol-related events exceeded the sum of their separate effects. Among men, we observed 289 (95% confidence interval = 123, 457) extra events per 100,000 person-years owing to education-alcohol interaction (P < 0.001). Similarly, among women, we observed 239 (95% confidence interval = 90, 388) extra events per 100,000 person-years owing to this interaction (P < 0.001). CONCLUSIONS High alcohol consumption is associated with a higher risk of alcohol-related medical events among those with low compared with high education. This interaction may be explained by differences in vulnerability and drinking patterns across educational groups.See video abstract at, http://links.lww.com/EDE/B267.