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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.

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.

Aim Resuming drinking is a main contributant to recurrence in alcoholic pancreatitis. We assessed current clinical practice in the Netherlands regarding alcohol in managing patients with a first episode of acute alcoholic pancreatitis. Methods A survey was distributed to 35 hospitals affiliated with the Dutch Pancreatitis Study Group. We evaluated current support based on various components of brief interventions, the participation of psychosocial healthcare providers, the cooperation with the primary care physicians and the presence of a protocol and its implementation. Results The response rate was 100% (n = 35). Psychoeducation is the most frequently performed intervention in current support treatment (97% of hospitals). In 17% of hospitals, healthcare providers with a psychosocial background routinely participate in current support treatment; 37% of hospitals create an individual treatment plan in which goals regarding alcohol cessation are specified and only 46% of hospitals provide the primary care physician with specific discharge information; 31% of hospitals indicate that the treatment is uniformly performed within their division of Gastroenterology. Protocols are available in 3% of the hospitals surveyed. Opportunities to involve the patient’s social network were not given sufficient priority. Conclusion Among Dutch hospitals, there is no routine management strategy with regard to enhancing treatment for heavy alcohol use in alcoholic pancreatitis patients. There is a need to test a validated support program in randomized studies. Meanwhile, possible opportunities for effecting change are often missed.

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.

Alcoholic chronic pancreatitis (ACP) is a fibroinflammatory disease of the pancreas. However, metabolic basis of ACP is not clearly understood. In this study, we evaluated differential pancreatic injury in hepatic alcohol dehydrogenase-deficient (ADH(−)) deer mice fed chronic ethanol (EtOH), chronic plus binge EtOH, and chronic plus binge EtOH and fatty acid ethyl esters (FAEEs, nonoxidative metabolites of EtOH) to understand the metabolic basis of ACP. Hepatic ADH(−) and ADH normal (ADH(+)) deer mice were fed Lieber-DeCarli liquid diet containing 3% (wt/vol) EtOH for 3 mo. One week before the euthanization, chronic EtOH-fed mice were further administered with an oral gavage of binge EtOH with/without FAEEs. Blood alcohol concentration (BAC), pancreatic injury, and inflammatory markers were measured. Pancreatic morphology, ultrastructural changes, and endoplasmic reticulum (ER)/oxidative stress were examined using H&E staining, electron microscopy, immunostaining, and/or Western blot, respectively. Overall, BAC was substantially increased in chronic EtOH-fed groups of ADH(−) versus ADH(+) deer mice. A significant change in pancreatic acinar cell morphology, with mild to moderate fibrosis and ultrastructural changes evident by dilatations and disruption of ER cisternae, ER/oxidative stress along with increased levels of inflammatory markers were observed in the pancreas of chronic EtOH-fed groups of ADH(−) versus ADH(+) deer mice. Furthermore, chronic plus binge EtOH and FAEEs exposure elevated BAC, enhanced ER/oxidative stress, and exacerbated chronic EtOH-induced pancreatic injury in ADH(−) deer mice suggesting a role of increased body burden of EtOH and its metabolism under reduced hepatic ADH in initiation and progression of ACP. NEW & NOTEWORTHY We established a chronic EtOH feeding model of hepatic alcohol dehydrogenase-deficient (ADH(−)) deer mice, which mimics several fibroinflammatory features of human alcoholic chronic pancreatitis (ACP). The fibroinflammatory and morphological features exacerbated by chronic plus binge EtOH and FAEEs exposure provide a strong case for metabolic basis of ACP. Most importantly, several pathological and molecular targets identified in this study provide a much broader understanding of the mechanism and avenues to develop therapeutics for ACP.

Background: Previous genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions. Methods: We conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants. Results: Variants at the CTRC (p = 1.22 × 10−21) and SPINK1 (p = 6.59 × 10−47) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220. Conclusions: A shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression.

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.

Long-term alcohol consumption and gene mutations are the most important causes of chronic pancreatitis. In addition to mutations in acinar genes, such as digestive enzymes and their inhibitors, defects in genes that primarily or exclusively affect the duct cells have also been described in recent years. Genetic changes are found not only in patients with a positive family history (hereditary pancreatitis) but also in so-called idiopathic and, to a lesser extent, in alcoholic chronic pancreatitis. The coming years will likely show that there are very complex interactions between environmental influences and numerous genetic factors.Langjähriger Alkoholkonsum und Genmutationen sind die wichtigsten Ursachen einer chronischen Pankreatitis. Neben Mutationen in azinären Genen wie Verdauungsenzymen und deren Inhibitoren sind in den letzten Jahren auch genetische Defekte beschrieben worden, die vornehmlich oder ausschließlich die Gangzellen betreffen. Genveränderungen finden sich nicht nur bei Patienten mit positiver Familienanamnese (hereditäre Pankreatitis), sondern auch bei sogenannter idiopathischer und – in geringerem Maße – bei alkoholischer chronischer Pankreatitis. In den nächsten Jahren wird sich wahrscheinlich zeigen, dass sehr komplexe Interaktionen zwischen Umwelteinflüssen und zahlreichen genetischen Faktoren bestehen.

The role of fatty acid ethyl esters (FAEEs) during human alcoholic pancreatitis is unknown. We compared FAEEs levels with their nonesterified fatty acids (NEFAs) precursors during alcohol intoxication and clinical alcoholic pancreatitis. The pathophysiology underlying FAEEs increase and their role as diagnostic biomarkers for alcoholic pancreatitis was investigated.A prospective blinded study compared FAEEs, NEFAs, and ethanol blood levels on hospitalization for alcoholic pancreatitis (n = 31), alcohol intoxication (n = 25), and in normal controls (n = 43). Serum FAEEs were measured at admission for nonalcoholic pancreatitis (n = 75). Mechanistic cell and animal studies were done.Median FAEEs were similarly elevated during alcohol intoxication (205 nmol/L; 95% confidence interval [CI], 71.8-515 nmol/L, P.001) and alcoholic pancreatitis (103.1 nmol/L; 95% CI, 53-689 nmol/L, P.001) vs controls (1.7 nmol/L; 95% CI, 0.02-4.3 nmol/L) or nonalcoholic pancreatitis (8 nmol/L; 95% CI, 1.1-11.5 nmol/L). Alcoholic pancreatitis increased serum NEFAs (1024 ± 710 μmol/L vs 307 ± 185 μmol/L in controls, P.05). FAEEs comprised 0.1% to 2% of the parent NEFA concentrations. FAEES correlated strongly with NEFAs independent of ethanol levels in alcoholic pancreatitis but not during alcohol intoxication. On receiver operating characteristic curve analysis for diagnosing alcoholic pancreatitis, the area under the curve for serum FAEEs was 0.87 (95% CI, 0.78-0.95, P.001). In mice and cells, alcohol administration transiently increased all FAEEs. Oleic acid ethyl ester was the only FAEE with a sustained increase up to 24 hours after intraperitoneal oleic acid plus ethanol administration.The sustained, alcohol-independent, large (20- to 50-fold) increase in circulating FAEEs during alcoholic pancreatitis results from their visceral release and mirrors the 2- to 4-fold increase in parent NEFA. The large areas under the curve of FAEEs on receiver operating characteristic curve analysis supports their role as alcoholic pancreatitis biomarkers.

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: Excessive alcohol consumption has long been known to be the primary cause of chronic pancreatitis (CP) but genetic risk factors have been increasingly identified over the past 25 years. The scale and scope of gene-alcohol interactions in CP nevertheless remain unclear. Methods: All studies that had obtained genetic variant data concurrently on alcoholic CP (ACP) patients, non-ACP (NACP) patients and normal controls were collated. Employing normal controls as a common baseline, paired ORACP and ORNACP (odds ratios associated with ACP and NACP, respectively) values were calculated and used to assess gene-alcohol interactions. Results: Thirteen variants involving PRSS1, SPINK1, CTRC, CLDN2, CPA1, CEL and CTRB1-CTRB2, and varying from very rare to common, were collated. Seven variants had an ORACP > ORNACP, which was regarded as an immediate indicator of gene-alcohol interactions in CP. Variants with an ORACP < ORNACP were also found to interact with alcohol consumption by virtue of their impact on age at first pancreatitis symptoms in ACP. Conclusions: This study revealed evidence for extensive gene-alcohol interactions in CP. Our findings lend support to the hypothesis that alcohol affects the expression of genetically determined CP and highlight a predominant role of weak-effect variants in the development of ACP.

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.

BACKGROUND AND OBJECTIVES: Chronic pancreatitis (CP) is a debilitating fibro-inflammatory disease with a profound impact on patients' quality of life (QOL). We investigated determinants of QOL in a large cohort of CP patients.METHODS: This was a multicentre study including 517 patients with CP. All patients fulfilled the EORTC QLQ-C30 questionnaire. Questionnaire responses were compared to results obtained from a general reference population (n = 11,343). Demographic characteristics, risk factors (smoking and alcohol consumption), pain symptoms, disease phenotype (complications) and treatments were recorded. A multivariable regression model was used to identify factors independently associated with QOL scores.RESULTS: Included patients had a mean age of 56.3 ± 12.8 years, 355 (69%) were men and 309 (60%) had alcohol aetiology. Compared to the reference population, patients with CP had lower global health status (50.5 vs. 66.1; p < 0.001) as well as reduced scores for all functional scales (all p < 0.001). Additionally, CP patients reported a higher burden for all symptom items, with pain being the most prominent complaint (all p < 0.001). Constant pain (coefficient -11.3; p = 0.02), opioid based pain treatment (coefficient -19.7; p < 0.001) and alcoholic aetiology (coefficient -5.1; p = 0.03) were independently associated with lowered global health status. The final multivariable model explained 18% of the variance in global health status.CONCLUSIONS: Patients with CP have significantly lower QOL compared to a population-based reference population. Factors independently associated with a lowered QOL are constant pain, opioid based pain treatment and alcohol aetiology. However, these factors only explain a fraction of QOL and additional factors need identification.

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.