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Recurrent acute pancreatitis (RAP) is a clinically significant problem globally. The etiology remains unclear in approximately 10% to 15% of patients despite a thorough workup. Data on natural history and efficacy of treatments are limited. We aimed to establish criteria for diagnosis, evaluate the causative factors, and arrive at a consensus on the appropriate workup and management of patients with RAP. The organizing committee was formed, and a set of questions was developed based on the current evidence, controversies, and topics that needed further research. After a vetting process, these topics were assigned to a group of experts from around the world with special interest in RAP. Data were presented as part of a workshop on RAP organized as a part of the annual meeting of the America Pancreatic Association. Pretest and Posttest questions were administered, and the responses were tabulated by the current Grades of Recommendation Assessment, Development and Evaluation system. The consensus guidelines were established in the format of a diagnostic algorithm. Several deficiencies were identified with respect to data on etiology, treatment efficacies, and areas that need immediate research.

Objectives: The aim of this study was to study intestinal fatty acid binding protein (i-FABP) as a potential biomarker in predicting severity of acute pancreatitis (AP)., Methods: In a prospective multicenter cohort study, plasma levels of i-FABP were measured in 402 patients with AP. Severity of AP was determined based on the 1992 Atlanta Classification., Results: Admission levels of plasma i-FABP were significantly higher in patients with pancreatic necrosis, in patients having systemic complications, in patients treated invasively, in patients treated in the intensive care unit, in patients with severe AP, and in deceased patients. Plasma i-FABP levels on admission yielded an area under curve (AUC) of 0.732 in discriminating patients with or without pancreatic necrosis and AUC of 0.669 in predicting severe AP. Combination of levels of i-FABP and venous lactate on the day of admission showed higher discriminative power in severe AP-AUC of 0.808., Conclusions: Higher i-FABP levels on admission were associated with pancreatic necrosis, systemic complications, and severe AP. Low levels of i-FABP had a high negative predictive value for pancreatic necrosis and severe AP. Combination of levels of i-FABP and venous lactates on admission were superior to either of markers used alone in predicting severe AP.

Objectives: Severe acute pancreatitis is associated with peripancreatic morphologic changes as seen on imaging. Uniform communication regarding these morphologic findings is crucial for accurate diagnosis and treatment. For the original 1992 Atlanta classification, interobserver agreement is poor. We hypothesized that for the revised Atlanta classification, interobserver agreement will be better., Methods: An international, interobserver agreement study was performed among expert and nonexpert radiologists (n = 14), surgeons (n = 15), and gastroenterologists (n = 8). Representative computed tomographies of all stages of acute pancreatitis were selected from 55 patients and were assessed according to the revised Atlanta classification. The interobserver agreement was calculated among all reviewers and subgroups, that is, expert and nonexpert reviewers; interobserver agreement was defined as poor (≤0.20), fair (0.21-0.40), moderate (0.41-0.60), good (0.61-0.80), or very good (0.81-1.00)., Results: Interobserver agreement among all reviewers was good (0.75 [standard deviation, 0.21]) for describing the type of acute pancreatitis and good (0.62 [standard deviation, 0.19]) for the type of peripancreatic collection. Expert radiologists showed the best and nonexpert clinicians the lowest interobserver agreement., Conclusions: Interobserver agreement was good for the revised Atlanta classification, supporting the importance for widespread adaption of this revised classification for clinical and research communications.

Background: The recent development of two different severity classifications for acute pancreatitis has appropriately raised questions about which should be used. The aim of this paper is to review the two new severity classifications, outline their differences, review validation studies, and identify gaps in knowledge to suggest a way forward., Methods: A literature review was performed to identify the purposes and differences between the classifications. Validation studies and those comparing the two different classifications were also reviewed., Results: The Revised Atlanta Classification (RAC) and the Determinants Based Classification (DBC) both rely on assessment of local and systemic factors. The differences between the classifications provides opportunities for further research to improve the accuracy and utility of severity classification. This includes understanding how best to tailor severity classification to setting (e.g. secondary or tertiary hospital) and purpose (e.g. clinical management or research). A key difference is that the RAC does not consider infected pancreatic necrosis an indicator of severe disease. There is also the need to develop methods for the accurate non-invasive diagnosis of infected necrosis and evaluation of the characteristics of organ dysfunction in relation to severity and outcome., Conclusion: Further improvement in severity classification is possible and research priorities have been identified. For now, the decision as to which classification to use should be on the basis of setting, validity, accuracy, and ease of use., (Copyright © 2015 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Introduction: In acute pancreatitis, enteral nutrition (EN) reduces the rate of complications, such as infected pancreatic necrosis, organ failure, and mortality, as compared to parenteral nutrition (PN). Starting EN within 24 h of admission might further reduce complications., Methods: A literature search for trials of EN in acute pancreatitis was performed. Authors of eligible trials were requested to provide the data of all patients in the EN-arm of their trials. A meta-analysis of individual patient data was performed. The cohort of patients with EN was divided into patients receiving EN within 24 h or after 24 h of admission. Multivariable logistic regression, adjusting for predicted disease severity and trial, was used to study the effect of timing of EN on a composite endpoint of infected pancreatic necrosis, organ failure, or mortality., Results: Observational data from 165 individuals from 8 randomised trials were obtained; 100 patients with EN within 24 h and 65 patients with EN after 24 h of admission. In the multivariable model, EN started within 24 h of admission compared to EN started after 24 h of admission, reduced the composite endpoint from 45% to 19% (adjusted odds ratio [OR] of 0.44; 95% confidence interval [CI] 0.20-0.96). Within the composite endpoint, organ failure was reduced from 42% to 16% (adjusted OR 0.42; 95% CI 0.19-0.94)., Conclusions: In this meta-analysis of observational data from individuals with acute pancreatitis, starting EN within 24 h after hospital admission, compared with after 24 h, was associated with a reduction in complications., (Copyright © 2014 IAP and EPC. All rights reserved.)

This study aims to update the 1991 Atlanta Classification of acute pancreatitis, to standardize the reporting of and terminology of the disease and its complications. Important features of this classification have incorporated new insights into the disease learned over the last 20 years, including the recognition that acute pancreatitis and its complications involve a dynamic process involving two phases, early and late. The accurate and consistent description of acute pancreatitis will help to improve the stratification and reporting of new methods of care of acute pancreatitis across different practices, geographic areas, and countries., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background and Objective: The Atlanta classification of acute pancreatitis enabled standardised reporting of research and aided communication between clinicians. Deficiencies identified and improved understanding of the disease make a revision necessary., Methods: A web-based consultation was undertaken in 2007 to ensure wide participation of pancreatologists. After an initial meeting, the Working Group sent a draft document to 11 national and international pancreatic associations. This working draft was forwarded to all members. Revisions were made in response to comments, and the web-based consultation was repeated three times. The final consensus was reviewed, and only statements based on published evidence were retained., Results: The revised classification of acute pancreatitis identified two phases of the disease: early and late. Severity is classified as mild, moderate or severe. Mild acute pancreatitis, the most common form, has no organ failure, local or systemic complications and usually resolves in the first week. Moderately severe acute pancreatitis is defined by the presence of transient organ failure, local complications or exacerbation of co-morbid disease. Severe acute pancreatitis is defined by persistent organ failure, that is, organ failure >48 h. Local complications are peripancreatic fluid collections, pancreatic and peripancreatic necrosis (sterile or infected), pseudocyst and walled-off necrosis (sterile or infected). We present a standardised template for reporting CT images., Conclusions: This international, web-based consensus provides clear definitions to classify acute pancreatitis using easily identified clinical and radiologic criteria. The wide consultation among pancreatologists to reach this consensus should encourage widespread adoption.

Context: Wegener's granulomatosis is a systemic vasculitis with prominent involvement of the respiratory tract and kidney. An association between acute pancreatitis and Wegener's granulomatosis is rarely reported and is even rarer as the first presentation. This can result in diagnostic difficulty and may allow severe pancreatitis to develop with potentially poor outcome., Case Report: We report a rare case with fatal outcome of vasculitis consistent with Wegener's granulomatosis presenting as acute pancreatitis in a 20-year-old female. The patient was admitted with worsening abdominal pain associated with nausea and loss of appetite. Accepted causes of acute pancreatitis were excluded and granulomatous vasculitis of the pancreas was confirmed from immunological profile, computed tomography and histology. As the disease progressed the patient experienced cutaneous, pulmonary, renal and severe gut involvement. Thirteen months from diagnosis the patient died of multi-organ failure despite appropriate surgical and immunosuppressive therapy., Conclusion: Vasculitic disease of the pancreas is rare but should be considered when other causes have been appropriately ruled out. Careful radiological, immunological and histological diagnosis is necessary and early immunosuppressant therapy in conjunction with advice from immunologists is essential to avoid the poor outcome reported in this and other case reports.

Background: Severity prediction is difficult early in the course of acute pancreatitis. Markers of pancreatic injury, or inflammatory activation are candidate markers of severity. The aim of the present study was to assess predictive abilities of carboxypeptidase-B activation peptide (CAPAP-B) and soluble L-selectin (sL-selectin) using samples collected on admission to hospital., Methods: Patients with acute pancreatitis and disease (acute abdomen) and normal controls were studied. Samples were collected at admission and daily for 5 days. There were significant differences between mild and severe pancreatitis in urinary and plasma CAPAP-B on admission, C-reactive protein on day 3 and acute physiology and chronic health evaluation (APACHE)-II scores. Prediction of severity with CAPAP-B on admission was as good as with APACHE-II score after 48 h. Carboxypeptidase-B activation peptide was not raised in disease controls. By contrast, sL-selectin was lowered in all cases of acute pancreatitis, and in disease controls. There was no difference between mild and severe pancreatitis., Conclusion: Urinary CAPAP-B, a marker of acinar injury, can be used to predict severity of acute pancreatitis at the time of admission to hospital, but sL-selectin has no value in this regard. The extent of acinar injury may be a more important early marker of severity than markers of inflammatory activation.

Context: Release of oxygen free radicals is increased in acute pancreatitis, but whether this can be used to predict clinical severity is not known., Objective: This study assesses whether plasma concentrations of malondialdehyde (a marker of lipid peroxidation) and superoxide dismutase (an oxygen free radical scavenger) can be used to predict severity of acute pancreatitis., Patients: Fifty-one patients with acute pancreatitis and two control groups were recruited., Main Outcome Measures: Plasma levels of malondialdehyde and erythrocyte content of superoxide dismutase were measured at 0, 12, 24, 48, 72, 96 and 120 hours after admission. Acute physiology and chronic health evaluation (APACHE) II, Glasgow and Ranson scores were calculated. Acute pancreatitis severity was defined by Atlanta criteria. Premorbid antioxidant intake was assessed by dietary questionnaire., Results: Levels of malondialdehyde were raised in acute pancreatitis patients and increased in patients with severe compared with mild acute pancreatitis; 12 hours after admission plasma malondialdehyde was 4.42+/-0.54 micromol/L and 2.95+/-0.24 micromol/L in severe and mild pancreatitis, respectively (mean+/-SEM; P=0.007). Plasma malondialdehyde greater than 2.75 micromol/L at 12 hours after admission had high overall accuracy for predicting severe acute pancreatitis. Superoxide dismutase levels were found to decrease in acute pancreatitis but no substantial significant difference was demonstrated between severe and mild acute pancreatitis patients. There was no difference in pre-morbid antioxidant dietary intake between the mild and severe pancreatitis groups., Conclusion: Plasma malondialdehyde may be a helpful additional marker of severity in the very early stages of acute pancreatitis.

Background/aims: Obesity is considered a risk factor in patients with acute pancreatitis. However, the relationship between obesity and mortality in this disease has not been confirmed definitively even in a previous meta-analysis. Since the publication of our previous meta-analysis, one study has been reported about the prognostic value of obesity in acute pancreatitis. We have performed a new meta-analysis to confirm the relationship between obesity and the outcome of acute pancreatitis., Data Sources: A MEDLINE search using 'pancreatitis', 'obesity' and 'body mass index' as search terms., Review Methods: Clinical studies which investigated the prognostic value of obesity in acute pancreatitis with the following criteria: (a) inclusion of mild and severe acute pancreatitis; (b) use of body mass index (BMI) as the measure of obesity; (c) definition of obesity as BMI >or=30 kg/m(2); (d) definition of severity of acute pancreatitis according to the criteria established in the Atlanta Symposium. Five studies including patients with mild and severe acute pancreatitis and obesity measured by BMI were analyzed. The end points of the meta-analysis were the severity of acute pancreatitis, local complications, systemic complications and mortality. Pooled odds ratio (OR) and confidence intervals (CI) were calculated according to the Mantel-Haenszel method, and heterogeneity was assessed by the multiplicative inverse variance method., Results: Seven hundred and thirty-nine patients were included. There was no heterogeneity for the variables severity, systemic complications, local complications and mortality among the included studies. Severe acute pancreatitis was significantly more frequent in obese patients (OR 2.9, 95% CI 1.8-4.6). Furthermore, those patients developed significantly more systemic (OR 2.3, 95% CI 1.4-3.8) and especially local complications (OR 3.8, 95% CI 2.4-6.6). In this new analysis, mortality was also higher in obese patients (OR 2.1, 95% CI 1.0-4.8)., Conclusion: Obesity is not only a risk factor for the development of local and systemic complications in acute pancreatitis: it also increases the mortality of this disease.

Aims: To test the hypothesis that single nucleotide polymorphisms (SNPs) within genes (or their promoter regions) encoding cytokines, growth factors, and intercellular adhesion molecules modulate the risk of development of chronic pancreatitis (CP)., Methods: DNA was extracted from peripheral blood leucocytes or formalin fixed, paraffin wax embedded tissue from 53 patients with CP and 266 healthy controls. SNPs within the interleukin 1beta (IL-1beta), IL-6, IL-8, tumour necrosis factor alpha (TNFalpha) and vascular endothelial growth factor (VEGF) gene promoter regions and the transforming growth factor beta1 (TGFbeta1) and intercellular cell adhesion molecule 1 (ICAM-1) genes were genotyped by the amplification refractory mutation system polymerase chain reaction or 5' nuclease (Taqman) techniques. Patient-control comparisons were made using 2 x 2 contingency tables and chi2 analyses., Results: A non-significant decrease in the frequency of the IL-8 -251 AA genotype and a non-significant increase in the frequency of the ICAM-1 +469 GA genotype was seen in patients compared with controls. No associations were identified between SNPs in the promoter regions of the IL-1beta, IL-6, or TNFalpha proinflammatory cytokines genes or the TGFbeta1 and VEGF genes and susceptibility to CP., Conclusions: This preliminary study suggests that genetic polymorphism within several cytokine genes is unlikely to influence susceptibility to CP, but the possible role of IL-8 and ICAM-1 polymorphisms in the development of this disease requires further investigation.

Background and Aims: Chronic pancreatitis (CP) produces disabling symptoms and requires major clinical interventions over a number of years. There is consensus that quality-of-life (QoL) assessment should be part of assessing the treatment and outcome of CP. These symptoms and treatments resemble those of pancreatic cancer, for which there are validated QoL assessment instruments. The aim of our study was to assess the appropriateness of using the EORTC QoL assessment system for pancreatic cancer (the EORTC QLQ-C30 and QLQ-PAN26) for patients with CP, and to document important issues that affect QoL in these patients., Methods: A structured literature review was undertaken to determine current approaches to QoL in pancreatic disease. Sixty-six patients with newly diagnosed or treated CP were asked to complete the EORTC QLQ-C30 and QLQ-PAN26 in four countries (Germany, Italy, South Africa, and United Kingdom). Patients were asked to review the appropriateness of the content and structure of the instruments, during a directed interview. Standard psychometric tests were used to assess the reliability and validity of the instruments. Peer review was undertaken to review findings and adapt the QLQ-PAN26 on the basis of the responses obtained., Results: The literature review highlighted the potential value of the EORTC QLQ-C30 and identified the lack of a CP-specific instrument, which had been appropriately developed. There was overwhelming consensus among experts that the EORTC assessment system appeared suitable for use in CP patients. This was endorsed by all patients. Patients identified additional issues related to guilt about the use of alcohol and the burden of trying to abstain. All but one scale (jaundice) exhibited adequate internal consistency (r > 0.70) Construct validity of the QLQ-C30 and QLQ-PAN26 showed strong associations between conceptually related scales (r > 0.6, p < 0.001) and significantly discriminated between patients on the basis of performance status and requirement for opiate analgesia. Significant issues affecting QoL in CP patients, in addition to recognized symptoms of the disease, were fear of future health problems, difficulty sleeping, and fatigue., Conclusion: The EORTC QLQ-C30 and QLQ-PAN26 appear to be an appropriate assessment system for CP, with the addition of items to cover guilt about alcohol consumption, and the burden of abstention. Patients' QoL is adversely affected by the fear of future health problems, difficulty sleeping, and fatigue.

Background: In predicted severe acute pancreatitis, many patients develop organ failure and recover without local complications, and mortality is only 14-30%. It has been suggested that half of patients with progressive early organ failure may die, but there are no data to relate death or local complications to duration of early (week 1) organ failure., Aims: To determine mortality rates in patients with transient (<48 hours) and persistent (>48 hours) early organ failure and to show whether persistent organ failure predicts death or local complications., Patients: A total of 290 patients with predicted severe acute pancreatitis previously studied in a trial of lexipafant, recruited from 78 hospitals through 18 centres in the UK., Method: Manual review of trial database to determine: the presence of organ failure (Marshall score > or =2) on each of the first seven days in hospital, duration of organ failure, and outcome of pancreatitis (death, complications by Atlanta criteria)., Results: Early organ failure was present in 174 (60%) patients. After transient organ failure (n = 71), outcome was good: one death and 29% local complications. Persistent organ failure (n = 103) was followed by 36 deaths and 77% local complications, irrespective of onset of organ failure on admission or later during the first week., Conclusion: Duration of organ failure during the first week of predicted severe acute pancreatitis is strongly associated with the risk of death or local complications. Resolution of organ failure within 48 hours suggests a good prognosis; persistent organ failure is a marker for subsequent death or local complications.

Background: Trypsinogen activation peptide (TAP) may be an early marker of severe pancreatitis. Previous studies have included all patients with organ failure in the group with severe pancreatitis, although patients with transient organ failure may have a good prognosis. The aim of this study was to determine the value of urinary TAP estimation for prediction of severity of acute pancreatitis, and to validate use of several markers of prediction of severity against a new, stringent definition of severity., Methods: Patients with acute pancreatitis were recruited within 24 h of onset of symptoms. Urine and blood samples were collected for 24 h, and Acute Physiology And Chronic Health Evaluation (APACHE) II (24 h), Ranson (48 h) and Glasgow (48 h) scores were calculated. Severe acute pancreatitis was defined by the presence of a local complication or the presence of organ failure for more than 48 h., Results: Urinary TAP levels were significantly greater in patients with severe pancreatitis than in those with mild disease during the first 36 h of admission. The highest of three estimations of TAP in the first 24 h was as effective as APACHE II at 24 h in predicting severity. At 24 h after admission, urinary TAP was better than C-reactive protein (CRP) in predicting severity. The combination of TAP and CRP at 24 h allowed identification of high- and low-risk groups. The new definition of severity excluded 24 of 190 patients with transient organ failure; none of these patients died., Conclusion: Use of TAP improved early prediction of the severity of acute pancreatitis. Organ failure that resolves within 48 h does not signify a severe attack of acute pancreatitis., (Copyright 2004 British Journal of Surgery Society Ltd.)

This paper reviews the current practice of nutritional support in acute pancreatitis. Appropriate interventions depend on the severity and duration of the pancreatitis and its complications. Current trends are away from restriction of oral or enteral intake, instead preferring this route to parenteral administration if possible. The role of the gut mucosal barrier in the pathogensis of the systemic response in pancreatitis has led to attempts to use enteral nutritional support to prevent complications, in addition to meeting nutritional needs in patients with long-term severe illness. Many clinicians believe that the management of acute pancreatitis should start from the concept of "pancreatic rest." Based on a simple understanding of pancreatic physiology and a belief that further stimulation of the pancreas during an attack of pancreatitis would exacerbate the inflammatory process by releasing more enzymes, traditional teaching has been that it is necessary to avoid all oral intake to prevent any inappropriate stimulation of pancreatic enzyme production. Accordingly, patients with acute pancreatitis are often deprived of enteral nutrition, and may be given intravenous parenteral nutritional support. Such an approach to nutritional support needs to be revised, since evidence emerging from many recent studies consistently indicates that an enteral route of nutrition is far superior.

Background: The advent of specific therapeutic or preventive treatments for severe acute pancreatitis creates a need to determine the risk of complications for each individual. Scoring systems used in acute pancreatitis identify groups of patients at risk of complications, but the pancreatitis-specific scores require 48 h of hospital admission to give full information. The APACHE-II score is useful within 24 h, but ignores simple clinical features, such as obesity, known to predict severity. The aim of this study was to evaluate a combination of the APACHE-II score with an obesity score in patients with acute pancreatitis, to predict severity using information available during the first 24 h of hospital admission., Methods: Data were collected prospectively from 186 consecutive patients with acute pancreatitis, to allow calculation of the APACHE-II score and body mass index (BMI). BMI was categorised as normal (score = 0), overweight (BMI 26-30: score = 1), or obese (BMI >30: score = 2). A logistic regression model was used to identify factors significantly associated with complications (Atlanta criteria; 104 complications in 60 patients)., Results: Age, BMI and the acute physiology score independently predicted complications. Addition of the score for obesity to the APACHE-II score gave a composite score (APACHE-O) with greater predictive accuracy. At cut-off of >8, APACHE-O had sensitivity 82%, specificity 86%, positive predictive value 74%, negative predictive value 91% and overall accuracy 85%., Conclusions: This study confirms that age, obesity and APACHE-II measured in the first 24 h of hospital admission can predict complications in acute pancreatitis. Combination of the APACHE-II and obesity scores by simple addition improved categorical prediction of severity (mild or severe) in patients with acute pancreatitis., (Copyright 2004 S. Karger AG, Basel and IAP)

Background: Total enteral nutrition (TEN) within 48 h of admission has recently been shown to be safe and efficacious as part of the management of severe acute pancreatitis. Our aim was to ascertain the safety of immediate TEN in these patients and the effect of TEN on systemic inflammation, psychological state, oxidative stress, plasma glutamine levels and endotoxaemia., Methods: Patients admitted with predicted severe acute pancreatitis(APACHE II score >5) were randomised to total enteral (TEN; n = 8) or total parenteral nutrition (TPN; n = 9). Measurements of systemic inflammation (C-reactive protein), fatigue (visual analogue scale), oxidative stress (plasma thiobarbituric acid-reactive substances), plasma glutamine and anti-endotoxin IgG and IgM antibody concentrations were made on admission and repeated on days 3 and 7 thereafter. Clinical progress was monitored using APACHE II score. Organ failure and complications were recorded., Results: All patients tolerated the feeding regime well with few nutrition-related complications. Fatigue improved in both groups but more rapidly in the TEN group. Oxidative stress was high on admission and rose by similar amounts in both groups. Plasma glutamine concentrations did not change significantly in either group. In the TPN group, 3 patients developed respiratory failure and 3 developed non-respiratory single organ failure. There were no such complications in the TEN group. Hospital stay was shorter in the TEN group [7(4-14) vs. 10 (7-26) days; p = 0.05] as was time to passing flatus and time to opening bowels [1 (0-2) vs. 2 (1-5)days; p = 0.01]. The cost of TEN was considerably less than of TPN., Conclusion: Immediate institution of nutritional support in the form of TEN is safe in predicted severe acute pancreatitis. It is as safe and as efficacious as TPN and may be beneficial in the clinical course of this disease.

Pancreatic stellate cells mediate fibrosis in chronic pancreatitis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs)-1 and -2 are crucial modulators of fibrosis. Transforming growth factor-beta (TGF-beta) is a key regulator of extracellular matrix production and myofibroblast proliferation. We have examined MMP and TIMP synthesis by transformed cultured pancreatic stellate cells and their regulation by TGF-beta 1. By Northern analysis they expressed mRNAs for procollagen 1, TIMP-1, TIMP-2, and MMP-2. Expression of membrane type-1 MMP was confirmed by Western blotting. By immunohistochemistry these enzymes localized to fibrotic areas in human chronic pancreatitis. Active TGF-beta 1 constitutes 2 to 5% of total TGF-beta 1 secreted by pancreatic stellate cells; they express TGF-beta receptors I and II. Exogenous TGF-beta 1 (10 ng/ml) significantly increased procollagen-1 mRNA by 69% and collagen protein synthesis by 34%. Similarly TGF-beta 1 at 0.1, 1, and 10 ng/ml significantly reduced cellular proliferation rate by 37%, 44%, and 44%, respectively, whereas pan-TGF-beta-neutralizing antibody increased proliferation by 40%. TGF-beta1 (10 ng/ml) down-regulated MMP-9 by 54% and MMP-3 by 34% whereas TGF-beta 1-neutralizing antibody increased MMP-9 expression by 39%. Pancreatic stellate cells express both mediators of matrix remodeling and the regulatory cytokine TGF-beta 1 that, by autocrine inhibition of MMP-3 and MMP-9, may enhance fibrogenesis by reducing collagen degradation.

Background: Chronic pancreatitis is characterised clinically by early exocrine insufficiency, with diabetes mellitus occurring as a late phenomenon. This is mirrored pathologically by extensive acinar cell destruction and islet preservation. The mechanisms underlying this differential rate of cellular destruction are unknown., Aims: To test the hypothesis that acinar loss and islet preservation in chronic pancreatitis occurs due to differential epithelial kinetics and investigate the role of inflammatory cells and cell cycle associated molecules., Methods: Archival tissue from six chronic pancreatitis cases was compared with six normal controls using TUNEL and immunohistochemistry for CD3, CD20, CD68, MIB-1, Bcl-2, Bax, Fas, Fas ligand, retinoblastoma protein (Rb), and tissue inhibitor of metalloproteinases 1 (TIMP-1) and 2 (TIMP-2)., Results: The acinar cell apoptotic index (AI) and proliferation index were higher in chronic pancreatitis than controls. T lymphocytes diffusely infiltrated fibrous bands and acini but rarely islets. Acinar Bcl-2 expression exceeded islet expression in chronic pancreatitis and controls while Bax was strongly expressed by a subset of islet cells and weakly by centroacinar cells. Islet Fas and Fas ligand expression exceeded acinar expression in chronic pancreatitis and controls. Acinar Rb expression was higher in chronic pancreatitis than in controls. Islets in chronic pancreatitis and controls showed intense TIMP-1 and TIMP-2 expression., Conclusion: Apoptosis plays a significant role in acinar loss in chronic pancreatitis. Acinar Bcl-2 and islet Bax expression indicates complex AI control. Increased acinar Rb expression in chronic pancreatitis may differentially promote acinar loss. Fas ligand expression may be restricted to islet cell membranes through TIMP-1 expression and inhibit islet damage by promoting apoptosis of cytotoxic T lymphocytes.

Background: Deficiencies and lack of standardisation of the management of acute pancreatitis in the UK have been reported. National UK guidelines for the management of acute pancreatitis were published in 1998. However, implementation of national guidelines in other areas has been patchy, suggesting that evaluation of the uptake of the pancreatitis guidelines would be appropriate., Aim: Identification of current practice in the management of acute pancreatitis as reported by consultant surgeons, in order to determine how effectively the UK guidelines have been introduced into practice., Methods: A questionnaire was posted to 1,072 full members of the Association of Surgeons of Great Britain and Ireland. It consisted of 13 questions that aimed to identify the surgeon's practice in the management of patients with acute pancreatitis in relation to key points in the UK guidelines. We compared the practice of hepatobiliary and pancreatic (HBP) vs. non-HBP specialists, and teaching vs. non-teaching hospital surgeons using the chi(2) test., Results: Of 538 responses (50%), 519 were from consultant surgeons. 59 did not look after patients with acute pancreatitis and 89 (17%) had a HBP interest. There were differences between the recommendations in the guidelines and reported practice, particularly in the use of critical care resources and referral to specialist units. Of consultants looking after acute pancreatitis 371 (72%) were non-HBP specialists. There were significant overall differences between the practice of HBP specialists and non-specialists: in severity assessment (Glasgow and C-reactive protein vs. Ranson criteria); indication and timing of requesting computed tomography (routinely at 7-10 days vs. when clinically indicated); nutritional support (enteral feeding vs. no support), and in common bile duct assessment prior to cholecystectomy (intra-operative cholangiography vs. endoscopic retrograde cholangiopancreatography). There was no significant difference between practice in teaching and non-teaching hospitals., Conclusion: Implementation of national guidelines for the management of acute pancreatitis was greater in the practice of HBP specialists than non-specialists. This has implications for the rationale of creating guidelines, and for the strategies associated with their introduction., (Copyright 2002 S. Karger AG, Basel)

Background: Serious sepsis and major blunt trauma have adverse effects on body composition, physiological function and psychological state. The effect of severe acute pancreatitis on these groups of variables has not yet been reported., Methods: We have studied the effect of predicted severe acute pancreatitis (admission APACHE II score > or = 6) on body fat and mid arm muscle circumference (assessed by dual-energy X-ray absorptiometry and anthropometry), respiratory function (measured by spirometry and vitalography), voluntary muscle function (measured by hand dynamometry) and psychological state (measured by use of the hospital anxiety and depression score and visual analogue scale for fatigue) on admission, and three and seven days thereafter., Results: The median APACHE II score of the 15 patients (7 men) in this study was 10 (6-13). The patients showed significant improvement in respiratory function (FEV1 1.3, 1.6, 2.3 litres/s, p < 0.01; FVC 1.5, 2.0, 2.9 litres, p < 0.01; PEFR 304, 372, 409 litres/min, p = 0.01 but no change in voluntary muscle function (210, 205, 213 N, p = 0.41) over the 7-day study period. Psychological state improved in terms of fatigue (2.4, 4.2, 7.0, p < 0.01) and depression (6, 9, 4, p = 0.12) but not in anxiety (8, 6, 7, p = 0.07). Body fat measured by DEXA (17.3 kg on admission, 16.7 kg on day 7, p = 0.13) and the mid upper arm muscle circumference (262, 248, 251 mm, p = 0.10) did not change implying that energy and nitrogen balance over the 7-day study period was achieved., Conclusion: Predicted severe acute pancreatitis has an adverse effect on respiratory function and psychological state similar to that observed in serious sepsis. Improvement in these variables is apparent over 7 days of effective treatment. Further research is indicated to examine the effect of nutritional support on these variables.

Background: Platelet activating factor (PAF) is believed to amplify the activity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We tested the hypothesis that a potent PAF antagonist, lexipafant, could dampen SIRS and reduce organ failure in severe acute pancreatitis., Methods: We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6. Power calculations assumed that complications would be reduced from 40% to 24%. Secondary end points studied included severity of organ failure, markers of the inflammatory response, and mortality rate., Findings: Overall, 80/138 (58%) patients in the placebo group and 85/148 (57%) in the lexipafant group developed one or more organ failures. The primary hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new organ failure. Organ failure scores were reduced in the lexipafant group only on day 3: median change -1 (range -4 to +8) versus 0 (-4 to +10) in the placebo group (p=0.04). Systemic sepsis affected fewer patients in the lexipafant group (13/138 v 4/148; p=0.023). Local complications occurred in 41/138 (30%) patients in the placebo group and in 30/148 (20%) in the lexipafant group (20%; p=0.065); pseudocysts developed in 19 (14%) and eight (5%) patients, respectively (p=0.025). Deaths attributable to acute pancreatitis were not significantly different. Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p<0.05); however, absolute values were not different between the two groups., Interpretation: The high incidence of organ failure within 72 hours of the onset of symptoms undermined the primary hypothesis, and power calculations for future studies in severe acute pancreatitis will need to allow for this. Lexipafant had no effect on new organ failure during treatment. This adequately powered study has shown that antagonism of PAF activity on its own is not sufficient to ameliorate SIRS in severe acute pancreatitis

Background: The incidence of acute pancreatitis shows regional variations in the UK., Aims: To document the incidence and presentation of acute pancreatitis in hospitals in Wessex, and to audit the process and outcome of management of patients against the UK guidelines., Methods: A prospective survey was carried out of all patients with acute pancreatitis in a one year period, in eight geographically adjacent acute hospitals in the Wessex region., Results: 186 patients with acute pancreatitis were identified, an incidence of 152 per million in the adult population. Aetiology was: gallstones 33%, alcohol 20%, idiopathic 32%, other 15%. There were 60 severe cases with 17 deaths. Age and APACHE-II score had significant relations to outcome, but delay to admission, serum amylase level, aetiology, and sex did not. The mortality rate (9.1%) was within the audit standard of 10%. Some management goals were not met: in mild cases, only one third of patients with gallstone pancreatitis had definitive treatment within four weeks. In severe cases, there was poor use of objective severity stratification (19%), low admission rates to a high dependency unit or intensive care unit (67%), and only 33% of patients had computed tomography. Only seven of 17 patients with severe gallstone pancreatitis had an urgent endoscopic retrograde cholangiopancreatography., Conclusions: The incidence of clinically diagnosed acute pancreatitis in England continues to rise. Current management of acute pancreatitis is suboptimal when compared with evidence based UK guidelines but the mortality rate was within the guideline standard.

Background: The diagnosis, early assessment, and management of severe acute pancreatitis remain difficult clinical problems. This article presents the consensus obtained at a meeting convened to consider the evidence in these areas. The aim of the article is to provide outcome statements to guide clinical practice, with an assessment of the supporting evidence for each statement., Method: Working groups considered the published evidence in the areas of diagnosis, assessment of severity, nonoperative treatment, and surgical treatment of severe acute pancreatitis. Outcome statements were defined to summarize the conclusions on each point considered. The findings were discussed and agreed on by all participants. A careful assessment was made of the strength of the available evidence (proven, probable, possible, unproven, or inappropriate)., Findings and Conclusions: There is reliable evidence to support much current practice. Clear guidance can be given in most areas examined, and several areas were identified where further investigation would be helpful. Diagnosis using plasma concentrations of pancreatic enzymes is reliable. Rapid advances are taking place in the assessment of severity. Several new therapeutic strategies show real promise for the reduction of morbidity and mortality rates. Surgical debridement is required for infected pancreatic necrosis, but is less often necessary for sterile necrosis.

Background: Current surgical practice with regards to antibiotic prophylaxis in acute pancreatitis in the UK and Ireland was overviewed., Methods: The 1103 members of the Association of Surgeons of Great Britain and Ireland were surveyed by postal questionnaire. A total of 528 replies were received (48 per cent). Following exclusion of surgeons not treating patients with acute pancreatitis, analysis was carried out on 429 replies., Results: Respondents treated a median of 12 (interquartile range (i.q.r.) 10-20) patients per year with acute pancreatitis. Prophylactic antibiotic therapy was used by 88 per cent of responding surgeons, of whom 24 per cent used it in all cases. For surgeons professing selective use of antibiotics, the most common indication for use was in patients with prognostically severe disease. A cephalosporin was prescribed in 72 per cent of patients; cefuroxime was the single most common antibiotic. Combination therapy with metronidazole was used in 48 per cent of attacks. The median duration of antibiotic therapy was 5 (i.q.r. 5-7) days. An adverse drug reaction attributable to the use of prophylactic antibiotics was reported by 11 per cent of respondents., Conclusion: This study has established that a significant body of clinicians charged with the responsibility of treating acute pancreatitis use antibiotic prophylaxis in the initial treatment of patients with predicted severe disease.

The role of early endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy in acute pancreatitis is controversial. Recent randomised controlled trials mostly support the value of this procedure, but concerns remain as to its safety, efficacy and practicability. This debate critically assesses the evidence for and against the use of early ERCP in acute pancreatitis.

Introduction: Acute pancreatitis causes platelet-activating factor (PAF) to be released which induces systemic effects that contribute to circulatory disturbances and multiple organ failure. PAF has also been implicated as a key mediator in the progression of severe acute pancreatitis, which can lead to complications and unacceptably high mortality rates., Mode of Action of Paf in Acute Pancreatitis: Synthesis of PAF is sensitive to biologically active mediators seen in many inflammatory processes. PAF significantly potentiates pancreatic tissue damage; it causes serum amylase and lipase levels to rise significantly, causes scattered haemorrhages and may serve as a primary mediator of inflammation., Paf Antagonists: Several classes of compounds show significant PAF antagonisms, and all have shown significant local and systemic effects to reduce inflammatory changes. Only lexipafant, however, has been studied in human acute pancreatitis. Lexipafant specifically binds to the PAF receptor and is more potent than other PAF antagonists. In clinical trials lexipafant reduces organ failure and suppresses some aspects of the inflammatory response., Conclusion: Our understanding of the pathology of systemic complications, and of a central role of PAF in mediating an inappropriate inflammatory response has improved in recent years. Confirmation of clinical findings with lexipafant will indicate an effective new therapy for the treatment of severe acute pancreatitis.

We present a case of pancreatic malignancy which presented as chronic pancreatitis. The diagnostic difficulties are discussed. We recommend that when there is any doubt about a diagnosis of chronic pancreatitis with a pancreatic mass, then early resection is appropriate.

This study evaluates the effect of oral pancreatic enzyme supplements on pain, analgesic requirement and the incidence of complications in patients with acute pancreatitis. This double blind, prospectively randomised placebo controlled study included 23 patients. Pain was monitored using a visual analogue scale; the analgesic requirement was assessed with a numerical score. No significant differences were noted between the median (range) pain scores of patients who received placebo: 22 (17.1-58) and those who received enzymes: 23 (11.3-63). Hospital stay was 7 (5-10) days in patients on placebo and 8 (6-24) days in the enzyme group (p = 0.069). Analgesic requirements were: placebo 20 (6-60) and enzymes: 16 (0-63) (p = 0.56). This study has shown no beneficial effect of oral pancreatic enzyme supplements in the initial management of patients with acute pancreatitis.

Seventeen patients underwent surgery for alcohol-induced chronic pancreatitis. Three patients later presented with pyogenic liver abscess. The time interval between surgery and presentation with hepatic abscess varied from 6 weeks to 3.5 years. All patients were diabetic, the presentation was insidious and all made an uneventful recovery, two with percutaneous drainage and one with antibiotics alone. The aetiology of this uncommon complication is discussed.

This debate reviews the arguments in favour of surgical or non-surgical techniques for the management of pancreatic pseudocysts. Surgery provides definitive management and has a low risk of recurrence; pancreatic resection may be required to achieve this. Surgical treatment of pancreatic pseudocyst is safe, with little morbidity and low mortality, and surgical drainage allows biopsy of the cyst wall to exclude a cystic neoplasm of the pancreas. Percutaneous techniques have the advantage of low morbidity and mortality, with less discomfort to the patient than a surgical incision. In selected patients, a good result can be anticipated. The balance of the evidence suggests that both approaches are useful in different patients. Pseudocyst management should be tailored to each individual case.

This review examines the appropriate timing of intervention in acute pancreatitis. In gallstone pancreatitis, it is now clear that cholecystectomy during the primary admission carries no greater risk of complications than delayed cholecystectomy and enables earlier recovery to normal activity. This course of action pre-empts a second, possibly fatal attack of acute pancreatitis. Cholecystectomy should be done after the acute phase has settled, before discharge from hospital. Patients with gallstones should now be offered endoscopic sphincterotomy within 48 hours of admission. This approach is safe, and reduces the risk of complications. When complications develop, early necrosectomy is only indicated if conservative measures fail. Delayed (> 10 days) necrosectomy is appropriate if there is evidence of sepsis, or clinical failure to improve. Pancreatic pseudocysts can often be managed expectantly; a high proportion will resolve spontaneously. After a delay of 12 weeks, persistent cysts require evaluation by endoscopic pancreatography, which gives crucial information in the choice between percutaneous or surgical drainage of the pseudocyst. A patient with pancreatitis is usually treated under the care of a surgeon, who has traditionally taken the decision on the timing of any intervention, and has performed such intervention at open operation. Recently, the development of alternative techniques has enabled the surgeon to call on the skills of his colleagues in endoscopy and interventional radiology. However, the availability of these alternatives to surgery should not affect the timing of intervention unless it can be clearly shown that such a change in timing combined with the minimally invasive technique can improve the outcome for the patient. Intervention may be required to deal with gallstones in the gallbladder or in the bile duct, to deal with, or ideally prevent, the deleterious systemic effects of pancreatic and peripancreatic necrosis, or to drain a peripancreatic abscess. Peripancreatic fluid collections and pancreatic pseudocysts may also require either internal or external drainage to relieve symptoms or prevent complications.

In a prospective study of 50 children who were admitted on more than one occasion with undiagnosed abdominal pain, the serum amylase was found to be normal in every case. One case of acute pancreatitis was diagnosed in over 8000 admissions. Serum amylase estimation did not contribute to the management of children with recurrent abdominal pain, and acute pancreatitis is so rare that routine amylase estimations cannot be recommended in paediatric surgical practice.

This study compared national statistics for consumption of alcohol and dietary intake with the numbers of cases of chronic pancreatitis as recorded in a 10% sample of all hospital discharges (Hospital In-Patient Enquiry) and with the annual number of deaths. Hospital discharges for chronic pancreatitis became more common throughout the study period (7.0-11.1 discharges per million per year in 1960-4; 26.8-32.4 discharges per million per year in 1980-4). The most rapid increase was from 1975-82. The rate increased fourfold in men, but only twofold in women, and the increase began earlier in men (1976) than in women (1980). Annual deaths from chronic pancreatitis also rose progressively (46-70 in 1960-4; 64-91 in 1985-8). The annual per capita consumption of alcohol rose from 4.0-4.9 litres in 1960-4 to a peak of 7.7 litres in 1979; it has been relatively stable (6.9-7.6 litres) in 1980-8. Total dietary energy intake assessed in the National Food Survey fell progressively, with a correspondingly greater fall in carbohydrate intake, so that the energy contributions of fat and protein rose slightly, although total fat and protein consumption fell from 1965-9 to 1980-4. These changes were small in relation to total dietary intake and seemed to be unrelated to the changes in the numbers of chronic pancreatitis discharges. There was a close correlation (r = 0.96) between per capita alcohol consumption and the numbers of discharges with chronic pancreatitis six years later. This suggests that epidemiological trends in chronic pancreatitis in the United Kingdom might be predictable from population based statistics of alcohol consumption.

We reviewed our recent experience with management of 23 consecutive patients with acute necrotizing pancreatitis. All patients had documented necrotizing pancreatitis with parenchymal or peripancreatic necrosis. Our method of treatment has evolved from our previous approach of controlled open lesser sac drainage (marsupialization) to staged necrosectomy/debridement with delayed primary closure over drains. With this latter approach, hospital mortality was 4 of 23 patients (17 per cent), but significant morbidity still occurred in 12 of 23 patients (52 per cent). However, recurrent intra-abdominal abscess before discharge occurred in only one patient. We believe that this operative approach toward the severely ill patient with acute necrotizing pancreatitis who requires operative intervention will minimize the occurrence of intra-abdominal sepsis.

This study was performed to determine if a correlation exists between pancreatic parenchymal enhancement or lack thereof on contrast-enhanced CT and surgical evidence of pancreatic necrosis. Accurate CT assessment of pancreatic vascular perfusion would be helpful in preoperative planning before pancreatic debridement and necrosectomy. The CT scans and medical records were blindly and retrospectively reviewed in 13 patients with the operative diagnosis of pancreatic necrosis. In all cases, CT examinations preceded surgery within 72 hr. Surgical and pathologic findings served as the gold standards for the diagnosis of pancreatic necrosis. Seven (54%) of 13 patients had a region or regions of parenchymal necrosis within the head, body, and/or tail of the pancreas seen during surgery. All seven of these patients had no pancreatic enhancement on CT in at least one region of the pancreas (CT sensitivity = 100%). In four of the seven, two regions were found to be necrotic at surgery, but only one of the two segments did not enhance on CT scans. In three of the seven patients, lack of contrast enhancement on CT (no enhancement of the pancreatic head and body in two patients and throughout the gland in another) correlated with necrosis in the same regions at surgery. The remaining six (46%) patients, who had peripancreatic or small, focal, and/or superficial areas of pancreatic necrosis at surgery, had normal pancreatic enhancement on CT. Our results show that regions of pancreatic necrosis found surgically correlate with lack of enhancement of pancreatic parenchyma on CT. Peripancreatic necrosis and minor areas of focal or superficial parenchymal necrosis were not detected on CT.