Protease Activation and Inflammation in Acute Pancreatitis

Approximately 10—20 % of patients with acute pancreatitis (AP) develop a severe disease with high mortality and morbidity. Activation of pancreatic proteases, the inflammatory response and impaired pancreatic circulation are pathophysiological events that are important in order for the disease to develop. There is no specific treatment for severe AP, and no useful marker for predicting the severity of the disease upon admission to the hospital. In this thesis, markers of early pathophysiological events in AP are investigated, with emphasis on protease activation and inflammation. ProCarboxypeptidase B (proCAP) is a pancreatic proenzyme which, particularly in severe AP, is activated by trypsin thereby forming Carboxypeptidase B (aCAP ) and the activation peptide of proCarboxypeptidase B (CAPAP). An ELISA method for measurement of serum aCAP in patients with AP was developed, and aCAP was shown to inhibit fibrinolysis in vitro. This may contribute to formation of necrosis in AP. The prediction of severity and pathophysiology was studied in patients with mild (n=124) and severe (n=16) AP. Markers of protease activation (aCAP, CAPAP) and inflammation (Monocyte Chemoattractant protein-1 (MCP-1) and CRP) were found to be elevated within 24 hours in patients with severe AP. Protease activation decreased after 48 hours, yet inflammation persisted for a longer period of time. Markers of pancreatic leakage (proCAP) decreased with time without differences in patients with mild and severe AP. MCP-1 exhibited a good capacity at predicting severe AP upon hospital admission. CAPAP and aCAP may also be useful in predicting the degree of severity

Study Protocol of the ESAP Study: Endoscopic Papillectomy vs. Surgical Ampullectomy vs. Pancreaticoduodenectomy for Ampullary Neoplasm—A Pancreas2000/EPC Study

Background: Lesions of the Ampulla of Vater are a rare condition and represent <10% of peri-ampullary neoplasms. Nevertheless, ampullary adenomas have the potential for malignant transformation to ampullary carcinomas by an adenoma-to-carcinoma sequence. Thus, adequate patient selection and complete resection (R0) of non-invasive ampullary lesions either by endoscopic papillectomy (EP), surgical ampullectomy (SA), or pancreaticoduodenectomy (PD) is essential. Although PD was traditionally performed, recent studies reported considerable efficacy and fewer complications following EP and SA. Since consistent comparative data are lacking, the Endoscopic Papillectomy vs. Surgical Ampullectomy vs. Pancreaticoduodectomy (ESAP) study will provide evidence for a therapeutic standard and post procedure morbidity in ampullary lesions. Methods: International multicenter retrospective study. Adult patients (>18 years of age) who underwent SA or PD for ampullary neoplasm between 2004 and 2018 or EP between 2007 and 2018 will be evaluated. Main inclusion criteria are ampullary lesions strictly located to the ampulla. This includes adenoma, adenocarcinoma (T1 and T2), neuroendocrine tumors, gastrointestinal stroma tumors and other rare conditions. Exclusion criteria are peri-ampullary lesions, e.g., from the duodenal wall or the head of the pancreas, and interventions for tumor stages higher than T2. The main objective of this study is to analyze rates of complete resection (R0), recurrence and necessity for complementary interventions following EP, SA, and PD. Treatment-quality for each procedure will be defined by morbidity, mortality and complication rates and will be compared between EP, SA, and PD. Secondary objectives include outcome for patients with incomplete resection or initially understated tumors, lesions of the minor papilla, hereditary syndromes, neuroendocrine tumors, mesenchymal lesions, and other rare conditions. Additionally, we will analyze therapy by argon plasma coagulation and radiofrequency ablation. Furthermore, outcome in curative and palliative interventions can be distinguished. Conclusion: The ESAP study will provide evidence for therapeutic algorithms and data for the implementation of guidelines in the treatment of different types of ampullary tumors, including recurrent, or incomplete resected lesions

IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality

Acute lung injury (ALI) is an inflammatory disease with a high mortality rate. Although typically seen in individuals with sepsis, ALI is also a major complication in severe acute pancreatitis (SAP). The pathophysiology of SAP-associated ALI is poorly understood, but elevated serum levels of IL-6 is a reliable marker for disease severity. Here, we used a mouse model of acute pancreatitis–associated (AP-associated) ALI to determine the role of IL-6 in ALI lethality. Il6-deficient mice had a lower death rate compared with wild-type mice with AP, while mice injected with IL-6 were more likely to develop lethal ALI. We found that inflammation-associated NF-κB induced myeloid cell secretion of IL-6, and the effects of secreted IL-6 were mediated by complexation with soluble IL-6 receptor, a process known as trans-signaling. IL-6 trans-signaling stimulated phosphorylation of STAT3 and production of the neutrophil attractant CXCL1 in pancreatic acinar cells. Examination of human samples revealed expression of IL-6 in combination with soluble IL-6 receptor was a reliable predictor of ALI in SAP. These results demonstrate that IL-6 trans-signaling is an essential mediator of ALI in SAP across species and suggest that therapeutic inhibition of IL-6 may prevent SAP-associated ALI

Helicobacter pylori infection, chronic corpus atrophic gastritis and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort: a nested case-control study

The association between H. pylori infection and pancreatic cancer risk remains controversial. We conducted a nested case-control study with 448 pancreatic cancer cases and their individually matched control subjects, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, to determine whether there was an altered pancreatic cancer risk associated with H. pylori infection and chronic corpus atrophic gastritis. Conditional logistic regression models were applied to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs), adjusted for matching factors and other potential confounders. Our results showed that pancreatic cancer risk was neither associated with H. pylori seropositivity (OR = 0.96; 95% CI: 0.70, 1.31) nor CagA seropositivity (OR = 1.07; 95% CI: 0.77, 1.48). We also did not find any excess risk among individuals seropositive for H. pylori but seronegative for CagA, compared with the group seronegative for both antibodies (OR = 0.94; 95% CI: 0.63, 1.38). However, we found that chronic corpus atrophic gastritis was non-significantly associated with an increased pancreatic cancer risk (OR = 1.35; 95% CI: 0.77, 2.37), and although based on small numbers, the excess risk was particularly marked among individuals seronegative for both H. pylori and CagA (OR = 5.66; 95% CI: 1.59, 20.19, p value for interaction < 0.01). Our findings provided evidence supporting the null association between H. pylori infection and pancreatic cancer risk in western European populations. However, the suggested association between chronic corpus atrophic gastritis and pancreatic cancer risk warrants independent verification in future studies, and, if confirmed, further studies on the underlying mechanisms

Nya nationella riktlinjer för handläggning av akut pankreatit

This is a short report of the recently published Swedish guidelines for acute pancreatitis, which are based on international guidelines as well as original publications. The report covers diagnosis, classification, treatment and follow up for patients with acute pancreatitis. Early rehydration and goal-based fluid therapy is recommended as well as oral intake of food on demand. Risk factors for development of severe disease and organ failure should be considered already in the emergency unit. Abdominal computer tomography is generally not recommended the first 5-7 days from onset of symptoms. Antibiotic therapy is only recommended when there is suspicion of or a confirmed infection. If intervention is needed for patients with moderate or severe disease a minimal-invasive step-up approach is recommended. Endoscopic Retrograde Cholangiography is generally not recommended as a treatment in the acute phase of the disease. Identification and treatment of the etiology causing acute pancreatitis is essential to prevent new episodes of the disease

The role of citrulline, intestinal fatty acid–binding protein, and D-dimer as potential biomarkers in the diagnosis of internal herniation after Roux-en-Y gastric bypass

Background: Diagnosing internal herniation (IH) in Roux-en-Y gastric bypass (RYGB) patients with acute abdominal pain poses a diagnostic challenge. Diagnostic laparoscopy is often required for a definitive diagnosis. We hypothesized that intestinal ischemia biomarkers would aid in the diagnosing of IH. Objectives: To explore intestinal ischemia biomarkers in diagnosing IH. Setting: University Hospital, Sweden. Methods: Prospective inclusion of 46 RYGB patients admitted for acute abdominal pain between June 2015 and December 2017. Blood samples for analysis of citrulline, intestinal fatty acid–binding protein (I-FABP), and D-dimer were drawn <72 hours from admission and compared between patients with IH (n = 8), small bowel obstruction (SBO) (n = 5), other specified diagnoses (n = 12), or unspecified abdominal pain (n = 21). Levels of white blood cell count (WBC), C-reactive protein (CRP), and lactate at admission were compared. A prospective pain questionnaire for time of pain onset and level of pain at onset and at admission was analyzed. Results: None of the investigated biomarkers differed significantly between diagnosis categories. Most patients with IH had normal CRP, WBC, and D-dimer levels while their lactate levels were significantly lower (P = .029) compared with the rest of the cohort. Neither pain level nor pain duration differed between the groups. Conclusion: This study shows that citrulline, I-FABP, and D-dimer cannot be used to diagnose IH and indicates that CRP, D-dimer, and lactate are rarely elevated by an IH. Furthermore, pain intensity and duration cannot differentiate patients with IH. A diagnostic laparoscopy remains the gold standard to diagnose and rule out an IH

Motiverande samtal för att främja livsstilsförändringar hos personer med övervikt eller fetma - En litteraturstudie

Syftet med föreliggande litteraturstudie var att beskriva inom vilka områden motiverande samtal kan användas av personal inom hälso- och sjukvård i behandlingen av personer med övervikt eller fetma. Vidare var syftet att beskriva vilka förmågor personalen som använder motiverande samtal bör inneha och vilken inverkan motiverande samtal har för personer med övervikt eller fetma som avser genomgå livsstilsförändringar. Litteratur söktes i databaserna Medline via PubMed samt Cinahl, och samtliga 12 studier som utgör resultatet var från åren 2005-2010. Huvudresultatet i studien visade att hälso- och sjukvårdspersonal använder motiverande samtal till att implementera förändringar gällande kost, fysisk aktivitet, motivation samt tilltro till dessa i arbetet med personer med övervikt och fetma. Motiverande samtal kunde stärka dessa förändringar och det visade sig även vara ett bra komplement till beteendeinterventioner. Förmågor hos hälso- och sjukvårdspersonal, såsom empati, hade betydelse för hur personers livsstilsförändringar implementerades. Konklusionen var att personer med övervikt och fetma kan genomgå livsstilsförändringar, såsom förbättrad kosthållning samt ökad fysisk aktivitet, som främjar hälsa och leder till viktnedgång med hjälp av motiverande samtal.The aim of this study was to describe the areas in which motivational interviewing can be used by health care personnel in the treatment of persons with overweight or obesity. Furthermore, the aim was to describe what abilities the personnel using motivational interviewing should obtain and what impact motivational interviewing has for persons with overweight or obesity about to undergo lifestyle changes. Literature was searched in Medline through PubMed and Cinahl, and all 12 studies which represent the result were from year 2005-2010. The main result of the study showed that health care personnel are using motivational interviewing to implement changes in terms of diet, physical activity, motivation and belief in these in the work with persons with overweight and obesity. Motivational interviewing could strengthen these changes and is also proved to be a good supplement to behavioral interventions. Health care personnel abilities, such as empathy, had a meaning for how persons lifestyle changes were implemented. The conclusion was that persons with overweight and obesity could undergo lifestyle changes, such as improved diet and increased physical activity, which promote health and lead to weight loss through motivational interviewing