Clinical assessment and management of severe acute pancreatitis: a multi-disciplinary approach in the XXI century.

Acute pancreatitis (AP) is the most common gastrointestinal disorder requiring hospitalization, with a high rate of morbidity and mortality. Severe AP is characterized by the presence of persistent organ failure involving single or multiple organs. Clinical evolution, laboratory and radiological assessment are necessary to evaluate the prognosis and inform the management of AP. The onset of severe AP may be classified in two principal phases. The early phase, during the first week, is characterized by the activation of the auto-inflammatory cascade, gut dysbiosis, bacterial translocation, and the down-regulation of immune responses. The late phase is characterized by the development of local and systemic complications. Several old paradigms have been amended in the management of AP patients, such as the indication of nutrition, the use of antibiotic therapy, pain control strategies, and even the use of surgery. Real world evidence has shown that in the majority of cases a step-up approach is most effective. In this review, we discuss the clinical assessment and improvements to the management of patients with severe AP in a high volume center where a multi-disciplinary approach is performed.

Risk of Immune-Related Pancreatitis in Patients with Solid Tumors Treated with Immune Checkpoint Inhibitors: Systematic Assessment with Meta-Analysis.

We performed a systematic review and meta-analysis to determine the risk of immune-related pancreatitis associated with the treatment by immune checkpoint inhibitors (ICIs) for solid tumors. Eligible studies were selected from multiple databases including phase II/III randomized controlled trials (RCTs) with ICIs in solid tumor patients. The data were analyzed with Stata version 12.0 software. After excluding ineligible studies, a total of 15 clinical trials were considered eligible for the meta-analysis, which included 9099 patients. Compared with chemotherapy or placebo, the risk ratio (RR) for all-grade lipase elevation after CTLA-4 inhibitor treatment was 1.05 (95% confidence interval (CI): 1.01-2.24, p = 0.047). However, the risk for pancreatitis after ICI treatment in any subgroup was not significantly higher than that after control therapy. In addition, compared with ipilimumab/nivolumab alone, the RR for all-grade and high-grade lipase elevation under combination treatment of nivolumab and ipilimumab was 6.43 (95% CI: 1.43-28.99, p = 0.015) and 6.44 (95% CI: 1.39-29.79, p = 0.017), respectively, and the RR for all-grade amylase elevation under combination treatment was 6.08 (95% CI: 1.51-24.44, p = 0.011). Our meta-analysis has demonstrated that both CTLA-4 inhibitors alone and combination treatment of nivolumab and ipilimumab could increase the risk of amylase or lipase elevation, but not significantly increase the risk of pancreatitis when compared with controls.

[Pathophysiology and Assessment of IgG4-Related Disease--Focus on Autoimmune Pancreatitis].

IgG4-related disease is well-known, and while the functions of cytokines which affect IgG4 production are being clarified, it remains unclear what causes it. There are many clinicopathological characteristics of IgG4-related disease and, therefore, comprehensive criteria are used for diagnosis. Notably, histopathological findings are the most important of these, with which we cannot make a definite diagnosis. The model disease of an IgG4-related disease is autoimmune pancreatitis (AIP). Currently, AIP is classified into type 1 (AIP1) and type 2 (AIP2). AIP1 is IgG4-related while AIP2 is not. AIP1 sometimes has localized mass formation, making it difficult to distinguish between AIP1 and pancreatic cancer. Thus, upon biochemical and immunological examination, the IgG4 level is the most useful for the diagnosis, although the levels of IL-2R, ß2MG, C4, and monoclonal rheumatoid factor are also useful for the assessment of disease. In addition, histopathological findings are also important to diagnose AIP1. Typical AIP1 cases show lymphoplasmacytic infiltration including IgG4-positive plasma cells with storiform fibrosis. A careful analysis of cases with the typical features of IgG4-related disease will lead to the elucidation of the mechanism behind IgG4-related disease.

Use of the Japanese health insurance claims database to assess the risk of acute pancreatitis in patients with diabetes: comparison of DPP-4 inhibitors with other oral antidiabetic drugs.

This study was initiated to evaluate the association of acute pancreatitis (AP) with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with diabetes in Japan. A retrospective cohort study of a large medical and pharmacy claims database was performed to compare the incidence of AP among those receiving DPP-4 inhibitors and those receiving other oral antidiabetic drugs. The incidence of all AP and hospitalizations for AP was similar between the two groups. Previous exposure to DPP-4 inhibitors did not affect occurrence of AP in patients on other oral antidiabetic drugs. The Kaplan-Meier curve for time to AP was similar between the two groups, and was not affected by previous exposure to DPP-4 inhibitors. The Cox proportional hazard models showed the incidence of AP was not significantly higher in those receiving DPP-4 inhibitors. Despite numerous, important limitations related to claims database-based analyses, our results indicate that there is no increased risk of AP with use of DPP-4 inhibitors among patients with diabetes in Japan.

Mechanisms and assessment of IgG4-related disease: lessons for the rheumatologist.

Recognition of IgG4-related disease as an independent chronic inflammatory disorder is a relatively new concept; previously, the condition was thought to represent a subtype of Sjögren's syndrome. IgG4-related disease is characterized by elevated serum levels of IgG4 and inflammation of various organs, with abundant infiltration of IgG4-bearing plasma cells, storiform fibrosis and obliterative phlebitis representing the major histopathological features of the swollen organs. The aetiology and pathogenesis of this disorder remain unclear, but inflammation and subsequent fibrosis occur due to excess production of type 2 T-helper-cell and regulatory T-cell cytokines. The disease can comprise various organ manifestations, such as dacryoadenitis and sialadenitis (also called Mikulicz disease), type 1 autoimmune pancreatitis, kidney dysfunction and lung disease. Early intervention using glucocorticoids can improve IgG4-related organ dysfunction; however, patients often relapse when doses of these agents are tapered. The disease has also been associated with an increased incidence of certain malignancies. Increased awareness of IgG4-related disease might lead to consultation with rheumatologists owing to its clinical, and potentially pathogenetic, similarities with certain rheumatic disorders. With this in mind, we describe the pathogenic mechanisms of IgG4-related disease, and outline considerations for diagnosis and treatment of the condition.

Circulating cytokine levels in acute pancreatitis-model of SIRS/CARS can help in the clinical assessment of disease severity.

The aim of our study was to evaluate the pro- and anti-inflammatory cytokine response during acute pancreatitis and its predictive value on severity of disease. A hospital-based prospective clinical study was conducted. Twenty patients with acute pancreatitis were enrolled during a 12-month period. Plasma concentrations of TNF-α, IL-1ß, IL-6, and IL-10 were determined at days 1, 2, 3, 6, and 9. The patient population was analyzed by type of acute pancreatitis. Severity was defined according to the Atlanta criteria for assessing severity of acute pancreatitis. Clinical variables were recorded to patients classified in one of two groups: severe acute pancreatitis (SAP group) and mild acute pancreatitis (MILD group). Patients with SAP had significantly higher average levels of IL-6 compared to the MILD group patients (539.2 pg/L vs. 23.4 pg/L, p < 0.0001). Also, the values of IL-10 were significantly higher in patients with SAP (242.4 pg/L vs. 8.1 pg/L, p = 0.003). The values of TNF-α were not significantly different in both groups. The value of IL-6 and IL-10 showed a positive correlation (r = 0.7964, p < 0.0001). Although a relatively small sample of patients was used, we can conclude that the determination of the value of IL-6 and IL-10 can help in the clinical assessment of disease severity.

Autoimmune pancreatitis: current diagnostic criteria are suboptimal.

BACKGROUND AND AIMS: The preoperative diagnosis of autoimmune pancreatitis (AIP) is difficult, given its similar clinical presentation to pancreatic cancer. The aims of the study are to describe our center's experience with AIP and apply the Japanese AIP diagnostic criteria to a cohort of patients with histologically-proven AIP in order to assess their performance characteristics. METHODS: A prospective pathology database was queried for AIP patients who were evaluated and/or treated at Johns Hopkins Hospital from 2002 to 2009. AIP histology was defined by the presence of lymphoplasmacytic infiltration, periductal inflammation, fibrosis, and periphlebitis. Imaging, clinical, and biochemical data were analyzed. RESULTS: Thirty patients had pancreatic resection with pathological confirmation of AIP. Imaging revealed pancreatic mass (45%), focal prominence without mass lesion (24%), diffuse enlargement (17%), and normal pancreas (14%). Twenty-four patients underwent an endoscopic retrograde cholangiopancreatography and/or magnetic resonance cholangiopancreatography, and 4/24 (17%) had pancreatic ductal narrowing or irregularity. Extrapancreaticobiliary organ involvement was found in 6% (n = 2) of patients. Biliary strictures were present in 87% of patients. Of 16 patients who underwent preoperative tissue biopsy, 10 had non-diagnostic pathology, five had cellular atypia, and one had AIP. Serum immunoglobulin G4 (IgG4) levels were elevated in 12 of 29 (41%) patients. Three (10%) patients had evidence of extrapancreatic manifestations of AIP. When applying the Japanese criteria to the 27 patients who had serum IgG4 measurement, preoperative biopsy, and cross-sectional abdominal imaging, only 44% of the patients would have been diagnosed accurately. CONCLUSIONS: When applied to a highly-selected single-center referral population in the USA, current Japanese guidelines for the diagnosis of AIP are found to have suboptimal sensitivity.

IgG4-related sclerosing cholangitis and autoimmune pancreatitis: histological assessment of biopsies from Vater's ampulla and the bile duct.

BACKGROUND AND AIM: Autoimmune pancreatitis is commonly associated with immunoglobulin (Ig) G4-related sclerosing cholangitis (IgG4-SC). The discrimination between IgG4-SC and pancreatobiliary malignancies or primary sclerosing cholangitis (PSC) is now an important issue. The present study was carried out to examine the usefulness of endoscopic biopsies from Vater's ampulla and the bile duct to diagnose IgG4-SC. METHODS: The present study included 29 IgG4-SC patients (26 with both pancreatitis and cholangitis, and 3 with cholangitis only), 6 PSC patients, and 27 pancreatobiliary carcinoma patients. All patients underwent endoscopic biopsies from Vater's ampulla and the common bile duct. Biopsied specimens were histologically examined using immunostaining for IgG4. RESULTS: For the ampullary and bile duct biopsies, the IgG4-SC samples had a significantly greater number of IgG4-positive plasma cells than the PSC or pancreatobiliary carcinoma specimens. In addition, bile duct biopsies from five patients (17%) with IgG4-SC showed diffuse inflammatory cell infiltration with irregular fibrosis corresponding to the histological features of lymphoplasmacytic sclerosing pancreatocholangitis. Based on the threshold of 10 IgG4-positive plasma cells per high power field, the diagnostic rates of the ampullar and bile duct biopsies were both 52% (15/29 cases). Twenty-one patients (72%) had more than 10 IgG4-positive plasma cells in at least one biopsy. The bile duct biopsy was significantly valuable for IgG4-SC patients with swelling of the pancreatic head. CONCLUSION: The present study suggested that ampullar and bile duct biopsies are useful for diagnosing IgG4-SC.

Review of 67 patients with autoimmune pancreatitis in Korea: a multicenter nationwide study.

OBJECTIVES: The ideal diagnostic criteria of autoimmune pancreatitis (AIP) are still challenging. Therefore, we investigated the clinical features of AIP in Korea and assessed the clinical use of new Korean diagnostic criteria. METHODS: We reviewed 67 patients with AIP enrolled in 16 hospitals via a multicenter study. The diagnosis was confirmed according to the Korean diagnostic criteria that included pancreatic imaging, laboratory findings, histopathology, and response to steroid. RESULTS: Mean age of the patients was 56 years, and 73% were men. Obstructive jaundice (52%) was the most common symptom, and 14 patients (21%) had other organ involvement. Fifty-four patients (81%) revealed diffuse swelling of the pancreas. Either immunoglobulin (Ig)G or IgG4 was elevated in 76%. According to the Korean criteria, 65 patients had definite diagnostic criteria, and 2 patients had probable criteria. Fifteen patients were fulfilled with image, serological, and histopathologic criteria, and 4 patients could be diagnosed with image and steroid responsiveness. Ten patients experienced recurrent attacks of AIP during the mean 20-month follow-up. CONCLUSIONS: Among 67 cases of AIP, either IgG or IgG4 was elevated in 76% of patients, and 14 patients (21%) had other organ involvement. New Korean diagnostic criteria are useful for diagnosis of AIP.

Serum adhesion molecules in acute pancreatitis: time course and early assessment of disease severity.

OBJECTIVES: To evaluate the adhesion molecule time course in the early phases of acute pancreatitis and to explore the usefulness of these proteins in assessing the severity of the disease. Fifteen consecutive acute pancreatitis patients (10 patients with the mild and 5 with the severe disease) admitted to the hospital within 6 hours after the onset of pain and 15 age- and sex-matched healthy subjects. METHODS: Vascular cell adhesion molecule 1, intercellular adhesion molecule 1, E-selectin, P-selectin, and L-selectin were quantified on hospital admission and for the following 2 days. RESULTS: Acute pancreatitis patients had vascular cell adhesion molecule 1 and P-selectin concentrations significantly lower and L-selectin concentrations significantly higher than the healthy subjects. Only E-selectin was significantly higher in severe than in mild disease (P = 0.029); a value of E-selectin ranging from 3.83 to 3.92 ng/mL was the best cutoff value for differentiating severe from mild acute pancreatitis (sensitivity: 60.0%, specificity: 90.0%, cases correctly classified: 80%). E-selectin and P-selectin entered the multivariate logistic regression analysis, and a score was calculated showing a sensitivity of 93.3% and a specificity of 86.7% in identifying the patients with severe pancreatitis. CONCLUSIONS: This score seems to be useful for the early assessment of the severity of acute pancreatitis.

2004 MacLean-Mueller prize enteral or parenteral nutrition for severe pancreatitis: a randomized controlled trial and health technology assessment.

BACKGROUND: The optimal route of nutrition in severe pancreatitis is controversial. Parenteral nutrition (PN) is preferred, but enteral nutrition (EN) promises to attenuate inflammation and prevent sepsis. We hypothesized that EN was at least equivalent to PN in reducing inflammation, providing effective nutrition and being cost-effective. METHODS: We conducted a randomized controlled trial comparing PN to EN in pancreatitis in an academic, multi-institutional, tertiary care health system. We screened 728 consecutive patients. Twenty-eight patients with a Ranson's score greater than 2 who did not tolerate clear fluids 4 days after admission were randomized: 18 to PN and 10 to EN. Both groups were provided daily 105 kJ (25 kcal)/kg and 1.5 g/kg of protein, respectively, until they could tolerate a regular diet. RESULTS: C-reactive protein in EN patients was reduced by 50% 5 days faster than PN patients (Wilcoxon test, p = 0.09). Both groups received a similar number of kilojoules and achieved near normal prealbumin and 24-hour urinary nitrogen values. Neither regimen caused a change in cholecystokinin levels. Overall mortality was 4.9% (3 patients in the PN group). In 5 patients (4 PN, 1 EN) there were infected pancreatic collections. Nine EN patients dislodged the nasojejunal tube. EN had an average cost of dollar 1375 per patient compared with dollar 2608 for PN (p = 0.08). After sensitivity analysis, EN cost dollar 957 compared with dollar 2608 for PN (p = 0.03). CONCLUSIONS: EN or PN is safe and provides adequate nutrition in severe pancreatitis. EN shows a trend toward faster attenuation of inflammation, with fewer septic complications and is the dominant therapy in terms of cost-effectiveness. This study favours EN for nutritional support in severe pancreatitis.