American College of Gastroenterology Guidelines: Management of Acute Pancreatitis.

Acute pancreatitis (AP), defined as acute inflammation of the pancreas, is one of the most common diseases of the gastrointestinal tract leading to hospital admission in the United States. It is important for clinicians to appreciate that AP is heterogenous, progressing differently among patients and is often unpredictable. While most patients experience symptoms lasting a few days, almost one-fifth of patients will go on to experience complications, including pancreatic necrosis and/or organ failure, at times requiring prolonged hospitalization, intensive care, and radiologic, surgical, and/or endoscopic intervention. Early management is essential to identify and treat patients with AP to prevent complications. Patients with biliary pancreatitis typically will require surgery to prevent recurrent disease and may need early endoscopic retrograde cholangiopancreatography if the disease is complicated by cholangitis. Nutrition plays an important role in treating patients with AP. The safety of early refeeding and importance in preventing complications from AP are addressed. This guideline will provide an evidence-based practical approach to the management of patients with AP.

Isotretinoin and inflammatory bowel disease: trial lawyer misuse of science and FDA warnings.

Based on the Food and Drug Administration Adverse Event Reporting System (FAERS), the FDA and Hoffman La Roche issued warnings of a possible causal association between isotretinoin and inflammatory bowel disease. While scientists studied the association, trial lawyers used the courts to award large sums of money to plaintiffs despite the absence of clear scientific evidence of a causal effect. In this Issue of the Journal, a well-designed, large pharmaco-epidemiologic study shows no association. The story of isotretinoin highlights the problems that occur when the FAERS is used in litigation prior to further study and scientific analysis.

American College of Gastroenterology guideline: management of acute pancreatitis.

This guideline presents recommendations for the management of patients with acute pancreatitis (AP). During the past decade, there have been new understandings and developments in the diagnosis, etiology, and early and late management of the disease. As the diagnosis of AP is most often established by clinical symptoms and laboratory testing, contrast-enhanced computed tomography (CECT) and/or magnetic resonance imaging (MRI) of the pancreas should be reserved for patients in whom the diagnosis is unclear or who fail to improve clinically. Hemodynamic status should be assessed immediately upon presentation and resuscitative measures begun as needed. Patients with organ failure and/or the systemic inflammatory response syndrome (SIRS) should be admitted to an intensive care unit or intermediary care setting whenever possible. Aggressive hydration should be provided to all patients, unless cardiovascular and/or renal comorbidites preclude it. Early aggressive intravenous hydration is most beneficial within the first 12-24 h, and may have little benefit beyond. Patients with AP and concurrent acute cholangitis should undergo endoscopic retrograde cholangiopancreatography (ERCP) within 24 h of admission. Pancreatic duct stents and/or postprocedure rectal nonsteroidal anti-inflammatory drug (NSAID) suppositories should be utilized to lower the risk of severe post-ERCP pancreatitis in high-risk patients. Routine use of prophylactic antibiotics in patients with severe AP and/or sterile necrosis is not recommended. In patients with infected necrosis, antibiotics known to penetrate pancreatic necrosis may be useful in delaying intervention, thus decreasing morbidity and mortality. In mild AP, oral feedings can be started immediately if there is no nausea and vomiting. In severe AP, enteral nutrition is recommended to prevent infectious complications, whereas parenteral nutrition should be avoided. Asymptomatic pancreatic and/or extrapancreatic necrosis and/or pseudocysts do not warrant intervention regardless of size, location, and/or extension. In stable patients with infected necrosis, surgical, radiologic, and/or endoscopic drainage should be delayed, preferably for 4 weeks, to allow the development of a wall around the necrosis.

Drug-Induced Acute Pancreatitis: An Evidence-Based Classification (Revised).

INTRODUCTION: Drug induced acute pancreatitis is a difficult diagnosis for clinicians. We previously published an "Evidence-Based Classification System" on Drug-Induced Acute Pancreatitis widely used by clinicians to assist in the identification of drugs. Unfortunately, this prior analysis based only on published case reports has been misunderstood. The prior review did not include studies with higher evidentiary value, such as randomized trials, case-control studies, and/or pharmacoepidemiologic studies. The use of the prior classification system has led to many patients being inappropriately labeled as having drug-induced acute pancreatitis. We now propose a "Revised" Evidence- Based Classification System for the purpose of determining which drugs cause acute pancreatitis based on the Grading of Recommendations, Development, and Evaluation criteria. METHODS: A search of the English Language literature was performed to identify all case reports with medication and/or drug induced acute pancreatitis. We divided the drugs implicated as causing acute pancreatitis into four groups based on the quality of evidence as defined by GRADE quality parameters. RESULTS: Although 141 drugs were identified in the literature as causing acute pancreatitis, only 106 drugs published in the literature as causing acute pancreatitis were high quality case reports. Only 3 drugs had evidence as causing acute pancreatitis from randomized controlled clinical trials, including 6-mercaptopurine and azathioprine. DISCUSSION: The vast majority of drugs implicated as causing acute pancreatitis in the literature have low or very low quality of evidence supporting those claims.

The role of antibiotics in the management of patients with acute necrotizing pancreatitis.

Our understanding of the role of antibiotics in the management of patients with pancreatic necrosis has changed over the past 5 years. Initial studies suggested that antibiotics were useful in preventing infection of necrosis, septic complications, and mortality in patients with acute pancreatitis; however, more recent, better-designed studies established that prophylactic antibiotics are not helpful. In the absence of infection, sterile necrosis is treated conservatively. With insufficient evidence to recommend antibiotics, these agents should be reserved to treat established infection of pancreatic necrosis. Infected necrosis is treated by targeting microbes with pancreatic-penetrating antibiotics (eg, carbapenems, quinolones in combination with metronidazole, or high-dose cephalosporins). If the patient with infected necrosis remains septic or deteriorates, surgical intervention should be performed urgently. Stable patients with infected necrosis can be managed more conservatively in a closely monitored environment. Recent studies suggest that many patients can clear the infection with antibiotics, but even if they do not clear the infection, delay in surgery decreases the mortality rate. Delaying surgery by using antibiotics may allow use of less invasive procedures if drainage is needed. The timing and method of interventions must be individualized based on the patient's condition, anatomic complications, patient's preference after informed consent, and expertise available at the institution.

Fluid Collections and Pseudocysts as a Complication of Acute Pancreatitis.

Pseudocysts evolve from fluid collections and/or disruptions of the pancreatic duct. They may occur secondary to acute pancreatitis, pancreatic trauma, or chronic pancreatitis. Lacking the clinical information, radiologists may inappropriately call a fluid collection or any cystic lesion a pseudocyst. With no clear history of acute pancreatitis or chronic pancreatitis, this is rare. Complications include infection, intracystic hemorrhage, or rupture. Pseudocysts can become painful, especially with chronic pancreatitis, and can cause early satiety and weight loss when their size affects the stomach and bowel. Symptomatic pseudocysts can successfully be drained with via surgical, radiologic, or endoscopic drainage.

Acinar cell injury induced by inadequate unfolded protein response in acute pancreatitis.

Acute pancreatitis (AP) is an inflammatory disorder of pancreatic tissue initiated in injured acinar cells. Severe AP remains a significant challenge due to the lack of effective treatment. The widely-accepted autodigestion theory of AP is now facing challenges, since inhibiting protease activation has negligible effectiveness for AP treatment despite numerous efforts. Furthermore, accumulating evidence supports a new concept that malfunction of a self-protective mechanism, the unfolded protein response (UPR), is the driving force behind the pathogenesis of AP. The UPR is induced by endoplasmic reticulum (ER) stress, a disturbance frequently found in acinar cells, to prevent the aggravation of ER stress that can otherwise lead to cell injury. In addition, the UPR's signaling pathways control NFκB activation and autophagy flux, and these dysregulations cause acinar cell inflammatory injury in AP, but with poorly understood mechanisms. We therefore summarize the protective role of the UPR in AP, propose mechanistic models of how inadequate UPR could promote NFκB's pro-inflammatory activity and impair autophagy's protective function in acinar cells, and discuss its relevance to current AP treatment. We hope that insight provided in this review will help facilitate the research and management of AP.

Recurrent Acute Pancreatitis: International State-of-the-Science Conference With Recommendations.

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.

Drug-induced acute pancreatitis: an evidence-based review.

The diagnosis of drug-induced acute pancreatitis often is difficult to establish. Although some medications have been shown to cause acute pancreatitis with a large body of evidence, including rechallenge, some medications have been attributed as a cause of acute pancreatitis merely by a single published case report in which the investigators found no other cause. In addition, some medications reported to have caused acute pancreatitis have obvious patterns of presentation, including the time from initiation to the development of disease (latency). There also appear to be patterns in the severity of disease. After reviewing the literature, we have classified drugs that have been reported to cause acute pancreatitis based on the published weight of evidence for each agent and the pattern of clinical presentation. Based on our analysis of the level of evidence, 4 classes of drugs could be identified. Class I drugs include medications in which at least 1 case report described a recurrence of acute pancreatitis with a rechallenge with the drug. Class II drugs include drugs in which there is a consistent latency in 75% or more of the reported cases. Class III drugs include drugs that had 2 or more case reports published, but neither a rechallenge nor a consistent latency period. Class IV drugs were similar to class III drugs, but only 1 case report had been published. Our analysis allows an evidence-based approach when suspecting a drug as causing acute pancreatitis.

Molecular biology, epidemiology, and the elusive nature of pancreatitis.

The myriad of presentations of pancreatitis can cause confusion and controversy among clinicians affecting the diagnosis, treatment, and research of patients with these disorders. Although the disease is best thought of as a spectrum with classic presentations, the underlying pathophysiologic reasons for the differences in manifestations remains unknown. In this issue of the Journal, LaRusch and colleagues provide an elegant study combining epidemiology and molecular biology to explain why some patients with pancreatitis develop fibrosis chronic pancreatitis. The implications of the findings add to the growing request to support large multidisciplinary, combined genetic, and epidemiologic studies in pancreatic disease.

Drug induced acute pancreatitis: does it exist?

As the incidence of acute pancreatitis continues to rise, establishing the etiology in order to prevent recurrence is important. Although the etiology of acute pancreatitis is not difficult in the majority of patients, almost a quarter of patients are initially labeled as having idiopathic acute pancreatitis. When confronted with a patient with acute pancreatitis and no clear etiology defined as an absence alcoholism, gallstones (ultrasound and/or MRI), a normal triglyceride level, and absence of tumor, it often appears reasonable to consider a drug as the cause of acute pancreatitis. Over 100 drugs have been implicated by case reports as causing acute pancreatitis. While some of these case reports are well written, many case reports represent poorly written experiences of the clinician simply implicating a drug without a careful evaluation. Over-reliance on case reports while ignoring randomized clinical trials and large pharmacoepidemiologic surveys has led to confusion about drug induced acute pancreatitis. This review will explain that drug induced acute pancreatitis does occur, but it is rare, and over diagnosis leads to misconceptions about the disease resulting in inappropriate patient care, increased litigation and a failure to address the true entity: idiopathic acute pancreatitis.

Diarrhoea due to pancreatic diseases.

The exocrine pancreas provides essential digestive enzymes necessary for the proper breakdown and absorption of ingested food in humans. Any disruption of this process can lead to malabsorption and resultant diarrhoea. Typically, disruption of over 90 percent of the pancreatic parenchyma is needed to result in diarrhoea. This disruption can result from widespread pancreatic necrosis in acute pancreatitis, fibrotic replacement of the parenchyma as seen in chronic pancreatitis and in patients with pancreatic cancer where normal tissue is replaced by tumour and/or the pancreatic duct becomes obstructed. Several uncommon tumours of the pancreas can also cause diarrhoea through the secretion of hormones. This article will explore each of these diseases, including the pathogenesis and treatment.

Decreased mortality in acute pancreatitis related to early aggressive hydration.

OBJECTIVE: Early aggressive intravenous hydration is believed to prevent morbidity and mortality by preventing intravascular volume depletion and maintaining perfusion of the pancreas possibly preventing pancreatic necrosis. The following study was initiated to determine the relationship between the observed decrease in mortality and the role of early aggressive hydration. METHODS: A consecutive series of patients with acute pancreatitis from a single community hospital in 1998 were compared to a consecutive series of patients with acute pancreatitis from the same institution in 2008. RESULTS: Significantly more patients developed pancreatic necrosis; 26 (15%) of 173 patients in 1998 compared to 4 (4%) of 113 patients in 2008. The mean rate of hydration was significantly higher in 2008 compared with that in 1998 (P = 0.02). In 1998, hydration was provided at 184 mL/h during the first 6 hours and 188 mL/h during the first 12 hours compared with 284 mL/h during the first 6 hours and 221 mL/h during the first 12 hours in 2008. There was a significant decrease in mortality in 2008 compared with that in 1998 (3.5% vs 12%, P = 0.03). CONCLUSIONS: The decrease in mortality seen in patients with acute pancreatitis during the last decade may be related to the increased aggressive hydration preventing pancreatic necrosis.

Efficacy of recombinant human interleukin-10 in prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis in subjects with increased risk.

OBJECTIVES: Pancreatitis is the most common major complication of endoscopic retrograde cholangiopancreatography (ERCP). Inflammatory cytokines are released during acute pancreatitis. Interleukin-10 (IL-10) is a potent inhibitor of cytokines and has been shown to attenuate pancreatitis in animal models and pilot human studies. This study aimed to determine whether prophylactic IL-10 administration reduces the frequency and/or severity of post-ERCP pancreatitis in high-risk patients. METHODS: A randomized, multicenter, double-blind, placebo-controlled study was conducted. Patients received IL-10 at a dose of either 8 or 20 microg/kg or placebo as a single intravenous injection 15 to 30 minutes before ERCP. Standardized criteria were used to diagnose and grade the severity of postprocedure pancreatitis. RESULTS: A total of 305 of the planned total enrollment of 948 patients were randomized. There was a 15%, 22%, and 14% incidence of post-ERCP pancreatitis in the IL-10 (8 microg/kg), IL-10 (20 microg/kg), and placebo treatment groups, respectively (P = 0.83 for IL-10 8 microg/kg vs placebo and 0.14 for IL-10 20 microg/kg vs placebo). Due to apparent lack of efficacy, the study was terminated at an interim analysis. CONCLUSIONS: : There was no apparent benefit of IL-10 treatment when compared with placebo in reducing the incidence of post-ERCP acute pancreatitis in subjects with increased risk.

Giant heterotopic pancreas presenting with massive upper gastrointestinal bleeding.

Heterotopic pancreas, or pancreatic rest, refers to extra-pancreatic tissue without an obvious vascular or anatomic connection with the pancreas. Although the frequency of heterotopic pancreatic tissue in autopsy series has been reported as high as 14%, clinical manifestations are rare [2]. Although common in the upper gastrointestinal tract, heterotopic pancreatic tissue rarely causes gastrointestinal bleeding. In a large case series following patients with heterotopic pancreatic tissue, only 7 of 212 patients had any evidence of bleeding [3]. We present a patient who presented with massive hematochezia found to have a giant heterotopic pancreas in the duodenum.