Alcoholic Chronic Pancreatitis Research Articles

Sedentary lifestyle, physical activity, and gastrointestinal diseases: evidence from mendelian randomization analysis

The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P<5×10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases. Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), Natural Science Foundation of Hunan Province (2021JJ30999), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), Swedish Research Council (Vetenskapsrådet, 2019-00977), Swedish Cancer Society (Cancerfonden), the Wellcome Trust (225790/7/22/Z), United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and National Institute for Health Research Cambridge Biomedical Research Centre (NHIR203312).

Genetic insights into across pancreatitis types: the causal influence of immunoglobulin G N-glycosylation variants on disease risk.

While a few case-control studies indicated a possible correlation of IgG N-glycosylation patterns with pancreatitis, their restricted sample sizes and methodologies prevented conclusive insights into causality or distinguishing traits across pancreatitis types. We conducted a two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between 77 IgG N-glycosylation traits and various types of pancreatitis, including acute pancreatitis (AP), chronic pancreatitis (CP), alcohol acute pancreatitis (AAP), and alcohol chronic pancreatitis (ACP). This analysis utilized summary-level data from genome-wide association studies (GWAS), employing methods such as IVW, MR-Egger, and weighted median. To ensure the robustness of our findings, several sensitivity analyses, including Cochran's Q statistic, leave-one-out, MR-Egger intercept, and MR-PRESSO global test were conducted. Our study uncovered the causal relationship between specific IgG N-glycosylation traits and various types of pancreatitis. Notably, an increase in genetically predicted IGP7 levels was associated with a decreased risk of developing AP. For CP, our data suggested a protective effect associated with higher levels of both IGP7 and IGP31, contrasting with increased levels of IGP27 and IGP65, which were linked to a heightened risk. Moreover, in the case of AAP, elevated IGP31 levels were causatively associated with a lower incidence, while higher IGP26 levels correlated with an increased risk for ACP. This study establishes causal relationship between specific IgG N-glycosylation patterns and varying risks of different pancreatitis forms, underscoring their potential as predictive biomarkers. These findings necessitate further exploration into the underlying mechanisms, promising to inform more personalized diagnostic and therapeutic strategies in pancreatitis management.

Point-shear wave elastography generated by acoustic radiation force impulse in chronic pancreatitis.

Transcutaneous point-shear wave elastography (p-SWE) performed using an acoustic radiation force impulse can be used to quantify pancreatic stiffness in chronic pancreatitis (CP). We aimed to evaluate its usefulness to diagnose and monitor CP. 175 participants were included in this prospective study including patients with CP (n=65), liver cirrhosis (LC; n=60), alcohol abuse (n=10) and healthy controls (n=40). Point-shear wave elastography of the pancreas was performed and quantified as median shear wave velocity (SWV). In the same way, p-SWE of the spleen served as a marker of portal hypertension. The M-ANNHEIM Severity score was used as global marker for disease activity in CP. Compared to healthy controls, pancreatic SWV was significantly elevated in CP (1.38 vs. 0.96m/s; p<0.0001, MWU-test). Pancreatic SWV was increased in alcoholic CP but not in hereditary CP. Receiver operating characteristic analysis revealed 1.2m/s as the optimal cut-off to identify non-heredity-CP subjects (90% specificity; 81% sensitivity; 92% positive predictive value). Pancreatic SWV correlated significantly with the M-ANNHEIM Severity score, severity of CP-typical complications (both p<0.05, linear regression analysis), morphological changes of the pancreas and need for hospital treatment (both p<0.05, MWU-test) but not with exocrine or endocrine insufficiency. Pancreatic SWV >1.7m/s was identified to predict M-ANNHEIM Severity score ≥11 points. Pancreatic SWV was also elevated in LC (1.42m/s; p<0.001), correlating with increased splenic SWV. Transcutaneous pancreatic p-SWE represents a bedside, cost-effective and non-invasive tool which adds valuable information to the process of diagnosing and monitoring CP. By portal hypertension, an increased pancreatic SWV must be expected.

Abstract B093: Alcoholic chronic inflammation driven CREB mediates acinar-to-ductal reprogramming and promote neoplastic progression

Abstract Introduction: Alcoholic chronic pancreatitis (ACP) is a progressive fibroinflammatory disease of the pancreas often characterized by extensive acinar cell injury leading to acinar-to-ductal metaplasia (ADM). However, the impact of ADM associated with ACP on the acceleration of oncogenic mutant Kras (Kras*)-driven tumorigenesis remains poorly understood. In this study, we aimed to unravel the underlying mechanism by which ACP-induced dysfunction and with Kras*, leads to the development of irreversible ADM and premalignant lesions that establish a tumor-permissive microenvironment for the emergence of high-grade pancreatic intraepithelial neoplasia (PanINs). Methods: ACP mice model was developed in acinar cell-specific Ptf1aCreERTM/+, Ptf1aCreERTM/+; LSL-KrasG12D/+ (KC), and genetic ablation of cyclic AMP response element-binding protein 1 (CREB) in KC (KCC−/−) mice crossed with or without R26R-EYFP reporter mice, and these mice were fed with alcohol-enriched or regular diet along with repetitive caerulein administration. Lineage tracing studies and acinar explants were employed to investigate the fate of adult acinar cells. ACP-induced mice were subsequently euthanized either 3 days or 21 days after ACP induction, the pancreas was collected for immunohistochemical analysis and examined for ADM, PanINs, fibrosis, and inflammation. To gain insights into the molecular mechanisms; kinase array analysis, acinar cell explant culture, Western blot and qPCR-based studies were conducted. Additionally, single-cell RNA sequencing (scRNA-seq) was employed to investigate cell-specific transcriptomic changes focusing on distinct cellular compartments. Results: Lineage tracing studies showed that ACP-induced ADM stems from direct transdifferentiating adult acinar cells to a ductal phenotype in Kras* mice. ACP induction with Kras* cooperatively provided a sustained Kras - dependent oncogenic program in inflammation-induced metaplastic progenitor cells. The upregulation of CREB accompanied this process of malignant transformation. CREB activation persists even after ACP withdrawal in KC mice compared to Ptf1aCreERTM/+ mice without mutant Kras. Acinar-specific CREB ablation attenuated advanced PanIN lesion development, impeding tumor progression in Kras* mice. Additionally, it reduced inflammation-induced tissue injury and facilitated acinar cell recovery. ScRNA-seq analysis revealed gene enrichment favoring acinar cell homeostasis and downregulation of ductal gene signatures in KCC−/− mice, further emphasizing CREB's pivotal role in modulating these cellular processes. Conclusion: Our findings demonstrate that Kras* sustains an irreversible ADM and PanIN through continuous activation of CREB. Additionally, we have identified that CREB mediates an oncogenic transcriptional program that drives tumor progression in the context of inflammation-induced disease. Importantly, our study reveals that ACP synergistically cooperates with Kras*-driven activated CREB, promoting the progression of ADM toward high-grade PanINs. Citation Format: Siddharth Mehra, Supriya Srinivasan, Anna Bianchi, Austin Dosch, Samara Singh, Vanessa Garrido, Iago De Castro Silva, Varunkumar Krishnamoorthy, Sudhakar Jinka, Jashodeep Datta, Nipun B. Merchant, Nagaraj Nagathihalli. Alcoholic chronic inflammation driven CREB mediates acinar-to-ductal reprogramming and promote neoplastic progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B093.

Chronic alcoholic pancreatitis with necrotising exacerbation and pseudocyst treated with homoeopathy: A Case Report

Chronic alcoholic pancreatitis with necrotising exacerbation and pseudocyst treated with homoeopathy: A Case Report

Comparison of sarcopenia in alcoholic and tropical chronic pancreatitis

Comparison of sarcopenia in alcoholic and tropical chronic pancreatitis

Impact of alcohol and smoking cessation on the course of chronic pancreatitis

OBJECTIVESAlcohol and nicotine are the two most important risk factors of chronic pancreatitis and they often occur together. It is still unclear how much they influence the severity of the disease and which of the two addictions should be treated with priority. METHODSWe performed a single-center, retrospective, cross-sectional study in a mixed medicosurgical cohort of 870 patients diagnosed with chronic pancreatitis (CP). We analyzed the impact of the drinking pattern and abstinence for alcohol and nicotine on the course of the disease. Patients with alcoholic CP were subdivided in I) patients with “life-time drinking history” (LTDH), II) “current drinkers” with current alcohol abuse without signs of LTDH, and III) “former drinkers” who stopped or reduced alcohol intake dramatically. RESULTSCompared to patients with LTDH, “former drinkers” had a lower rate of exocrine insufficiency (29% vs. 59%) and pseudocysts (33% vs. 49%), were more often relapse-free (37% vs. 5%) and had less abdominal pain. There was no correlation detected between the quantity of alcohol consumption and the severity or progression of the disease. Regarding nicotine, 29 pack years are the threshold for developing early stage of CP. Under nicotine abstinence, only slightly more patients were relapse-free (37% vs. 22%). In contrast, the cumulative amount of nicotine consumed correlated with overall disease severity and the development of pseudocysts. The need for surgery was increased with odds ratios of 1.8 for both, alcohol and nicotine abuse. CONCLUSIONSAlcohol cessation in chronic pancreatitis reduces exocrine insufficiency, abdominal pain and local complications. The effect of nicotine cessation is less pronounced in our cohort. However, nicotine abuse represents an important factor for the development of the disease.

Vitamin D3 analogue calcipotriol inhibits the profibrotic effects of transforming growth factor- β1 on pancreatic stellate cells

ObjectiveTo evaluate the inhibitory effect of vitamin D3 analogue calcipotriol (Cal) on the fibrosis of pancreatic stellate cells (PSCs) induced by TGF-β1 and the rationality of Cal use in alcoholic chronic pancreatitis (ACP). Material and methodsDouble-labeling immunofluorescence was used for the identification of VDR+PSCs in the pancreas of healthy controls (HC) and ACP patients. Van Gieson staining for examination of collagen fibers. RT-qPCR and Western Blot for determining the mRNAs and proteins of VDR, TGF-β1 and COL1A1 in the pancreas of ACP or in vitro PSCs. ELISA or LC-MS/MS for detection of serum TGF-β1 and COL1A1 or 25(OH)D3. The PSC line (RP-2 cell) was used for the determination of proteomic alterations in Cal plus TGF-β1 versus TGF-β1 and to examine the effect of VDR gene knockdown. ResultsEnhanced expression of VDR was detected in RP-2 cells stimulated with alcohol (ALC) plus Cal versus Cal alone and in PSCs in the pancreas of ACP versus HC. The increased VDR+PSCs were positively correlated with the levels of COL1A1 mRNAs or areas of collagen deposition in the pancreas of ACP. TGF-β1 was overexpressed in the pancreas of ACP and ALC-treated RP-2 cells while 25(OH)D3 level in serum was significantly decreased in ACP versus HC. Through a VDR-dependent mechanism, Cal antagonized 16 profibrotic proteins in TGF-β1-induced RP-2 cells that included 7 extracellular matrix components, 2 cytoskeletal proteins, 2 fibrosis-associated factors (RUNX1 and TRAF2), TIMP-1, CCN1, integrin α11, an adhesion scaffold protein (TGFB1i1) and an enzyme mediating TGF-β1-induced fibrogenesis (ENPP1). ConclusionThis study suggests that Cal administration may be a potential antifibrotic strategy via inhibiting TGF-β1-mediated PSC action during the development of ACP.

A CASE SERIES ON PANCREATICOPLEURAL FISTULA

A pancreaticopleural fistula (PPF) is a rare condition that causes thoracic symptoms such as dyspnea and chest pain secondary to exudative pleural effusions. While PPF is a very rare complication with only 52 cases reported between 1960 and 2007, they typically occur in patients who are male, middle aged, and have a history of chronic alcohol use and chronic pancreatitis (Aswani and Hira, 2015; Francisco et al., n.d.; Valeshabad et al., 2018; Ali et al., 2009). The fistula between the pancreas and pleural cavity causes large, rapidly accumulating, and recur- rent pleural effusions which cause symptoms that can be difficult to differentiate from other acute thoracic pathologies (Francisco et al., n. d.). As a result, it is essential that providers have a high index of suspicion for PPF in these appropriate populations. We present a case study with 2 patients who reported to our institute, to review the typical presentation, pathophysiology, and current approach to treatment of PPF.

Depression and 24 gastrointestinal diseases: a Mendelian randomization study

The causality of the association between depression and gastrointestinal diseases is undetermined. We conducted Mendelian randomization (MR) analyses to systematically explore the associations of depression with 24 gastrointestinal diseases. Independent genetic variants associated with depression at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analysis was conducted to explore the mediation effects of body mass index, cigarette smoking, and type 2 diabetes. After multiple-testing corrections, genetic liability to depression was associated with an increased risk of irritable bowel syndrome, non-alcohol fatty liver disease, alcoholic liver disease, gastroesophageal reflux, chronic pancreatitis, duodenal ulcer, chronic gastritis, gastric ulcer, diverticular disease, cholelithiasis, acute pancreatitis, and ulcerative colitis. For the causal effect of genetic liability to depression on non-alcoholic fatty liver disease, a substantial proportion was mediated by body mass index. Genetic predisposition to smoking initiation mediated half of effect of depression on acute pancreatitis. This MR study suggests that depression may play a causal role in many gastrointestinal diseases.

Dysregulated pancreatic lipid phenotype, inflammation and cellular injury in a chronic ethanol feeding model of hepatic alcohol dehydrogenase-deficient deer mice

AimsDysregulation of pancreatic fat and lipotoxic inflammation are common clinical findings in alcoholic chronic pancreatitis (ACP). In this study, we investigated a relationship between dysregulated pancreatic lipid metabolism and the development of injury in a chronic ethanol (EtOH) feeding model of hepatic alcohol dehydrogenase 1- deficient (ADH−) deer mice. MethodsADH− and hepatic ADH normal (ADH+) deer mice were fed a liquid diet containing 3 % EtOH for three months and received a single gavage of binge EtOH with/without fatty acid ethyl esters (FAEEs) one week before the euthanasia. Plasma and pancreatic tissue were analyzed for lipids including FAEEs, inflammatory markers and adipokines using GC–MS, bioassays/kits, and immunostaining, respectively. Pancreatic morphology and proteins involved in lipogenesis were determined by the H & E staining, electron microscopy and Western blot analysis. Key findingsChronic EtOH feeding in ADH− vs. ADH+ deer mice resulted in a significant increase in the levels of pancreatic lipids including FAEEs, adipokines (leptin and resistin), fat infiltration with inflammatory cells and lipid droplet deposition along with the proteins involved in lipogenesis. The changes exacerbated by an administration of binge EtOH with/without FAEEs in the pancreas of ADH− vs. ADH+ deer mice fed chronic EtOH suggest a metabolic basis for ACP. SignificanceThese findings suggest that the liver-pancreatic axis plays a crucial role in etiopathogenesis of ACP, as the increased body burden of EtOH due to hepatic ADH deficiency exacerbates pancreatic injury.

Genetic polymorphisms in phase II metabolizing enzymes in alcoholic and idiopathic chronic pancreatitis: Indian scenario.

To study polymorphisms in glutathione-S-transferases (GST-T1, GST-M1, GST-P1) and uridine-5'-diphosphate-glucuronosyl-transferases (UGT1A7) genes and the risk of developing chronic pancreatitis (CP) associated with these polymorphisms. This study included 49 alcoholic and 51 idiopathic chronic pancreatitis patients, 50 alcohol addicts and 50 healthy controls. Polymorphism(s) in GST-T1 and GST-M1 genes were assessed by multiplex polymerase chain reaction (PCR), while PCR-radiofrequency lesioning (RFLP) was employed to assess the same in GST-P1 and UGT1A7 genes. The differences in polymorphism frequency between groups and the risk of developing pancreatitis were assessed by the odds ratio. Strong association of the null genotype of GST-T1 with CP susceptibility was observed. Alcoholics with the Val allele of GST-P1 have higher chances of having pancreatitis. Idiopathic pancreatitis patients with higher age at the onset of pain were found to have the null genotype of GST-M1. Alcoholics with the null genotype of the GST-T1 gene and the Valine allele of the GST-P1 gene are at a higher risk of developing CP. Thus, genotyping of these genes may serve as an important screening tool for the identification of high-risk groups among alcoholics.

Inflammatory Conditions of the Pancreatobiliary Tree.

The Pancreatobiliary Pathology Society (PBPS) would like to thank Alain C. Borczuk, MD, and the Archives of Pathology & Laboratory Medicine for again highlighting our society by publishing 3 review articles based on the presentations at the PBPS companion society symposium, which was held at the 2021 United States and Canadian Academy of Pathology (USCAP) meeting. As always, PBPS's mission remains the education of surgical pathologists and cytopathologists about the importance of recent advances in this complex field, which will hopefully transform the way we practice pancreatobiliary pathology. The PBPS fosters excellence and international collaboration in education, research, and the global practice of pancreatobiliary pathology. PBPS became an official society in 2016 and a USCAP companion society in 2018. However, the sharing of knowledge, enthusiasm, and ideas in pancreatobiliary pathology actually began more than 20 years ago as an annual “Pancreas Club” luncheon, held during the annual USCAP meeting, which grew over the years and eventually became the PBPS. The first advisory council members of the Pancreas Club were Volkan Adsay, MD; Ralph Hruban, MD; David Klimstra, MD; Günter Klöppel, MD; and Giuseppe Zamboni, MD. Thanks to their continued dedication to pancreatobiliary pathology and contagious enthusiasm, many other pathologists interested in the field were attracted to join and motivated its transformation into the official 501c3 society that it is today (PBPath.org).Because of the COVID-19 pandemic, the 2021 annual USCAP meeting (and by extension the PBPS companion society meeting) was held virtually. The theme of the 2021 PBPS Companion Society Symposium was “Inflammatory Conditions of the Pancreatobiliary Tree.” It featured 1.5 hours of on-demand educational content provided by 4 invited speakers, as well as a live 30-minute question-and-answer session with the speakers and moderators, Michelle Reid, MD, MS, and Rondell Graham, MBBS. The theme of the 2021 meeting was updates on acute and chronic inflammatory conditions of the pancreatobiliary tree, and it featured 4 outstanding presentations by experts in the field (Barbara Centeno, MD, Vikram Deshpande, MD, Dr Klöppel, and Dr Zamboni) entitled (1) “Cytopathology of Inflammatory Lesions of the Pancreatobiliary Tree” (Centeno), (2) “IgG4-Related (Autoimmune) Pancreatitis” (Deshpande), (3) “Acute and Alcoholic Pancreatitis” (Klöppel), and (4) “Paraduodenal Pancreatitis” (Zamboni).All 4 presentations from the 2021 companion meeting have been converted into review articles and are featured in this issue of Archives of Pathology & Laboratory Medicine. In the first article, “Cytopathology of Inflammatory Lesions of the Pancreatobiliary Tree,” Dr Centeno reviews the cytopathology of inflammatory lesions of the pancreas and bile duct, including the different types of pancreatitis. The cytologic criteria useful for differentiating reactive ductal atypia from adenocarcinoma and other malignant mimics are also discussed, and the application of ancillary techniques for this differential diagnosis is emphasized. In addition, Dr Centeno reviews pertinent and best pathology practices in the application of ancillary immunohistochemical and molecular studies for the differential diagnosis of benign from malignant processes in the bile duct. The second article is entitled “Navigating the Challenges Associated With a Diagnosis of Autoimmune Pancreatitis and IgG4-Related Sclerosing Cholangitis” and is written by Dr Deshpande, along with his colleagues Osman Yilmaz, MD, and Karen Pinto, MBBS, DNB, FRCPath. In this article Drs Yilmaz, Pinto, and Deshpande examine the clinicopathologic features of type 1 and 2 autoimmune pancreatitis and immunoglobulin G4–related sclerosing cholangitis. They emphasize the use of a multimodal approach (clinical, radiographic, serologic, histopathologic, and immunohistochemical correlation) and highlight the distinctive overlapping qualities that can aid in diagnosing these entities and distinguishing them from other fibroinflammatory and/or neoplastic mimics. The authors also discuss diagnostic pitfalls and differential diagnoses and offer an approach to the interpretation of needle biopsies, including ampullary biopsies. The third article is entitled “Acute and Chronic Alcoholic Pancreatitis, Including Paraduodenal Pancreatitis.” It combines the talks of our third and fourth speakers, Dr Klöppel and Dr Zamboni. In this combined article, Drs Klöppel and Zamboni 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 role of alcohol overconsumption and related macroscopic changes and histopathologic characteristics are addressed. Pathologic findings that distinguish mild from severe pancreatitis, as well as a histologic staging system for chronic pancreatitis, are emphasized. The morphologic features of paraduodenal pancreatitis as well as the anatomic peculiarities associated with it are also described.We are extremely proud of our society and the continued contributions of its members to the field of pancreatobiliary pathology. We hope that you will enjoy these review articles highlighting the experts' perspectives on inflammatory conditions of the pancreatobiliary tree.

Altered MANF Expression in Pancreatic Acinar and Ductal Cells in Chronic Alcoholic Pancreatitis: A Cross-Sectional Study

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress response protein that plays an important role in pancreatic functions. As both alcohol and ER stress response proteins are involved in the pathogenesis of pancreatitis, we sought to investigate the expression of MANF in chronic alcoholic pancreatitis (CAP) and chronic non-alcoholic pancreatitis (CNP). A cohort of chronic pancreatitis tissues was gathered from routine surgical pathology (n = 77) and autopsy (n = 10) cases and tissue microarrays were created. Sampled tissues were reviewed and designated as representing CAP (n = 15), CNP (n = 58), or normal pancreatic tissue (NPT) (n = 27). MANF immunohistochemistry (IHC) and digital image analysis were performed to obtain an estimation of tissue fibrosis and an optical density (OD) of MANF IHC in ducts and acini for each case. The averaged values for these variables among histologic designations were compared. The amount of fibrous tissue of the combined CAP and CNP group (chronic alcoholic and non-alcoholic pancreatitis, CANP) exceeded that of the NPT group (70% vs. 34%, p < 0.0001). The MANF OD in ducts of CANP was significantly higher than that of NPT (0.19 vs. 0.10, p < 0.05). The MANF OD in ducts of CAP was significantly higher than that of CNP (0.27 vs. 0.17, p < 0.05). The MANF OD in acini of CAP was significantly lower than that in CNP (0.81 vs. 1.05, p < 0.05). Finally, there was a statistically significant positive relationship between the amount of fibrosis and MANF OD in ducts (p < 0.001). MANF expression was higher in ducts of CAP than CNP. In contrast, MANF expression in acini was lower in CAP than CNP and NPT. There was a positive correlation between fibrosis and MANF levels in the ducts.

Smoking, alcohol consumption, and 24 gastrointestinal diseases: Mendelian randomization analysis.

Whether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases. Genetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption. Genetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis, and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn's disease, and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, and acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 20 associations persisted after adjusting for genetically predicted alcohol consumption. Genetically predicted higher alcohol consumption was associated with increased risk of duodenal ulcer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain statistically significant after adjustment for genetic predisposition to smoking initiation. This study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases. The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society.

Pancreatic Cancer in Chronic Pancreatitis: Pathogenesis and Diagnostic Approach.

Chronic pancreatitis is one of the main risk factors for pancreatic cancer, but it is a rare event. Inflammation and oncogenes work hand in hand as key promoters of this disease. Tobacco is another co-factor. During alcoholic chronic pancreatitis, the cumulative risk of cancer is estimated at 4% after 15 to 20 years. This cumulative risk is higher in hereditary pancreatitis: 19 and 12% in the case of PRSS1 and SPINK1 mutations, respectively, at an age of 60 years. The diagnosis is difficult due to: (i) clinical symptoms of cancer shared with those of chronic pancreatitis; (ii) the parenchymal and ductal remodeling of chronic pancreatitis rendering imaging analysis difficult; and (iii) differential diagnoses, such as pseudo-tumorous chronic pancreatitis and paraduodenal pancreatitis. Nevertheless, the occurrence of cancer during chronic pancreatitis must be suspected in the case of back pain, weight loss, unbalanced diabetes, and jaundice, despite alcohol withdrawal. Imaging must be systematically reviewed. Endoscopic ultrasound-guided fine-needle biopsy can contribute by targeting suspicious tissue areas with the help of molecular biology (search for KRAS, TP53, CDKN2A, DPC4 mutations). Short-term follow-up of patients is necessary at the clinical and paraclinical levels to try to diagnose cancer at a surgically curable stage. Pancreatic surgery is sometimes necessary if there is any doubt.

Pathomorphological changes in experimental model of chronic alcohol and drug-induced pancreatitis in the rat

Aim of the research: The aim of the study to conduct the histomorphological study of structural and cellular changes in the tissues of the pancreas, adrenal gland, spleen, liver, kidney in experimental alcoholic and drug-induced pancreatitis. Materials and methods. A model of experimental alcoholic and drug-induced pancreatitis was created on white mongrel rats aged 2-3 months, weighing 25-30 g. The animals were divided into 3 groups (control group No. 1, comparison groups No. 2 and No. 3). A control group (n=10) that did not receive any substances. The second comparison group (n=10) was injected daily with 1 ml of 40% ethanol solution for 10 days. The third comparison group (n=10) was administered intragastric tyrosol daily at the rate of 5 mg per 100 g of body weight for 10 days. Withdrawal from the experiment was performed on the 10 th day from the beginning of the experiment. Laboratory animals were slaughtered by decapitation. Pancreas, spleen and liver, kidneys with adrenal glands were taken for pathomorphological examination. Research results and discussion. During histological examination of the pancreas on the 10th day of the experiment, no changes were noted in the control group, in comparison groups No. 2, No. 3, pathomorphological changes were noted, indicating an inflammatory and dystrophic process in the pancreas. During histological examination of tissues, complications in the liver, spleen, kidneys and adrenal glands were also observed on day 10. Conclusions. The above facts indicate that comparison group No. 2 developed chronic experimental alcoholic pancreatitis induced by ethanol solution; comparison group No. 3 induced experimental drug-induced pancreatitis. One of the main ways of endogenous insufficiency is the enteral pathway, the least dependent on pharmacological correction.

Пациент с хроническим калькулезным панкреатитом: задача со многими неизвестными

Aim. To describe a clinical case of a patient with diabetes mellitus in the outcome of chronic calcific pancreatitis. Key points. Chronic pancreatitis is a multifaceted disease complicating a great number of body systems work. Currently, the problem of post-pancreatitis diabetes mellitus is receiving more and more attention precisely because simultaneous decrease of the endo- and exocrine functions of the pancreas without timely correction is accompanied by concomitant metabolic disorders that lead to different complaints, hiding the underlying cause. In addition to the familiar to endocrinologists’ problem of correcting hyperglycemia, there is also the problem of exocrine pancreatic insufficiency and vitamin-mineral-protein deficiency. Our patient’s dysfunction of the pancreas was reflected in the appearance of secondary hyperparathyroidism with the formation of osteoporosis, decreased growth, and a pathological fracture. The presented clinical case demonstrates the variety and scale of complications that develop in a patient with chronic calculous pancreatitis. Conclusion. Careful history taking and a comprehensive examination of a patient with a long story of chronic alcoholic pancreatitis should contribute to the timely diagnosis and correction of diseases that develop due to a progressive loss of endo- and exocrine pancreatic function. Keywords: chronic calcific pancreatitis, pancreatic elastase, exocrine pancreatic insufficiency, secondary hyperparathyroidism, osteoporosis, diabetes mellitus.

High Clinical and Genetic Similarity Between Chronic Pancreatitis Associated With Light-to-Moderate Alcohol Consumption and Classical Alcoholic Chronic Pancreatitis

<h3>Background and Aims</h3> Heavy alcohol consumption and genetic factors represent the 2 major etiologies of chronic pancreatitis (CP). However, little is so far known about the clinical features and genetic basis of light-to-moderate alcohol consumption-related CP (LMA-CP). <h3>Methods</h3> A cross-sectional analysis was performed on 1061 Chinese CP patients between 2010 and 2015. CP was classified as classical alcoholic CP (ACP; n = 206), LMA-CP (n = 154), and idiopathic CP (ICP; n = 701). Clinical features and genetic characteristics (<i>PRSS1</i>, <i>SPINK1</i>, <i>CTRC</i>, <i>CFTR</i> variant status) were compared between the different groups. Odds ratios (ORs) with 95% confidence intervals were calculated to ascertain the combinatorial effect of alcohol consumption and gene mutation. <h3>Results</h3> Compared with ICP, the clinical features of LMA-CP were characterized by higher rates of developing pancreatic stones, pseudocyst, diabetes, and steatorrhea, which were similar to those associated with ACP. The prevalence of CP-related gene variants in LMA-CP was 38.3%, similar to ACP (39.8%), although significantly lower than ICP (56.2%). Alcohol consumption enhanced the risk of a poor clinical outcome, whereas genetic factors amplified alcohol's effects. Compared with ICP, LMA-CP and ACP were associated with a high risk of pancreatic stones (patients without variants, OR = 2.01 and 2.54; patients with variants, OR = 2.17 and 1.07), pseudocyst (patients without variants, OR = 1.03 and 1.43; patients with variants, OR = 1.67 and 2.14), diabetes mellitus (patients without variants, OR = 0.86 and 1.31; patients with variants, OR = 2.05 and 1.55), and steatorrhea (patients without variants, OR = 1.56 and 2.10; patients with variants, OR = 2.11 and 1.60). <h3>Conclusions</h3> Evidence was presented to show that LMA-CP was clinically and genetically similar to ACP but significantly different from ICP. Our findings provide support to the growing view that there is no safe level of alcohol consumption.

Usefulness of Endoscopic Ultrasound for the Detection of Asymptomatic Pancreatic Morphological Changes in Patients with Alcoholic Liver Disease: A Cross-sectional Study

Introduction: Although alcoholism is a common aetiological link between liver and pancreatic disorders, the frequency of coinciding pancreatic disease in patients with alcohol-related liver disease is not well understood. The present study mentions about the use of Endoscopic Ultrasound (EUS) with standardised criteria to assess asymptomatic or overt pancreatic pathology in patients with alcoholic liver disease. Aim: To determine the prevalence of asymptomatic Alcoholic Chronic Pancreatitis (ACP) in Indian patients affected by Alcoholic Liver Cirrhosis (ALC) using EUS. Materials and Methods: The present observational crosssectional study was conducted on patients attending the Outpatient Department of Gastroenterology at Santokba Durlabhji Memorial Hospital Cum Medical Research Institute, Jaipur, Rajasthan, India. A total of 35 patients were screened with alcoholic liver disease for pancreatic abnormalities using EUS. The patients were recruited for the study over a period of 12 months, from September 2013 to August 2014. The prevalence of chronic pancreatitis (CP) was determined, and abnormalities were graded according to the Rosemont criteria. The severity of alcoholic liver disease, as indexed by Child Pugh Scoring (CPS) and Model for End-stage Liver Disease (MELD), was evaluated for any association with endosonographic findings of CP. The influence of various clinico-demographic factors on alcoholic liver and pancreatic diseases was analysed using the PSS Inc. Chicago, IL program. Results: A total of 35 male patients, aged 28 to 65 years with a mean age of 46.97 years, fulfilled the inclusion criteria. EUS revealed a prevalence of CP in 20% of patients. Three patients showed changes suggestive of CP, of which two had ALC and one had Alcoholic Hepatitis (AH). Four patients were prioritised in categorised as indeterminate for CP, with three having cirrhosis and one having Alcoholic Fatty Liver (ALF). No significant influence of clinico-demographic profiles on the final outcome parameters was observed. The patient with endoscopic changes had a MELD score of 12.85±5.11 compared to patients without changes of ACP (19.1±5.71) (p=0.013). ALC was found to be inversely related to EUS changes of ACP. Conclusion: The EUS is an effective screening tool for evaluating pancreatic abnormalities in patients with alcoholic liver disease. The present study provides a comprehensive review of previous findings in light of the varying facts and figures. As there is still a lack of experimental animal models for ALC and ACP, studies of this kind may shed light on hidden links in disease pathology.