Phil A. Hart

Recent advances in autoimmune pancreatitis

Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that is characterized clinically by frequent presentation with obstructive jaundice, histologically by a dense lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to corticosteroid therapy. Two distinct diseases, type 1 and type 2 AIP, share these features. However, these 2 diseases have unique pancreatic histopathologic patterns and differ significantly in their demographic profiles, clinical presentation, and natural history. Recognizing the popular and long-standing association of the term AIP with what is now called type 1 AIP, we suggest using AIP solely for type 1 AIP and to acknowledge its own distinct disease status by using idiopathic duct-centric chronic pancreatitis (IDCP) for type 2 AIP. AIP is the pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD). The etiopathogenesis of AIP and IgG4-RD is largely unknown. However, the remarkable effectiveness of B-cell depletion therapy with rituximab in patients with AIP and IgG4-RD highlights the crucial role of B cells in its pathogenesis. IDCP is less commonly recognized, and little is known about its pathogenesis. IDCP has no biomarker but is associated with inflammatory bowel disease in ~25% of patients. Recently, the international consensus diagnostic criteria for AIP identified combinations of features that are diagnostic of both diseases. Both AIP and IDCP are corticosteroid responsive; however, relapses are common in AIP and rare in IDCP. Therefore, maintenance therapy with either an immunomodulator (eg, azathioprine, 6-mercaptopurine, or mycophenolate mofetil) or rituximab is often necessary for patients with AIP. Long-term survival is excellent for both patients with AIP and patients with IDCP.

Prophylactic antibiotics in necrotizing pancreatitis: a meta-analysis.

Purpose: Prophylactic antibiotics have been used in acute necrotizing pancreatitis with mixed results. This meta-analysis analyzes the effects of prophylactic antibiotics in necrotizing pancreatitis. Methods: Multiple databases and abstracts were searched for randomized trials comparing treatment with prophylactic antibiotics to treatment without prophylactic antibiotics in necrotizing pancreatitis. Prophylactic antibiotics’ effects were analyzed by calculating pooled estimates of mortality, infected pancreatic necrosis, length of hospital stay, nonpancreatic infections, and surgical intervention. Results: Seven studies (n = 429) met the inclusion criteria. Prophylactic antibiotics for acute necrotizing pancreatitis significantly decreased the length of hospital stay (P = 0.04) and the rate of nonpancreatic infections (P < 0.01). No significant differences were noted for mortality (P = 0.22), infected necrosis (P = 0.18), and surgical intervention (P = 0.40). Conclusions: Prophylactic antibiotics in necrotizing pancreatitis reduced the length of hospital stay and rate of nonpancreatic infections but did not decrease mortality, infected necrosis, or surgical intervention.

Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer

Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.

Morbid Obesity Is Associated With Adverse Clinical Outcomes in Acute Pancreatitis: A Propensity-Matched Study.

OBJECTIVES:Morbid obesity may adversely affect the clinical course of acute pancreatitis (AP); however, there are no inpatient, population-based studies assessing the impact of morbid obesity on AP-related outcomes. We sought to evaluate the impact of morbid obesity on AP-related clinical outcomes and health-care utilization.METHODS:The Nationwide Inpatient Sample (2007–2011) was reviewed to identify all adult inpatients (≥18 years) with a principal diagnosis of AP. The primary clinical outcomes (mortality, renal failure, and respiratory failure) and secondary resource outcomes (length of stay and hospital charges) were analyzed using univariate and multivariate comparisons. Propensity score-matched analysis was performed to compare the outcomes in patients with and without morbid obesity.RESULTS:Morbid obesity was associated with 3.9% (52,297/1,330,302) of all AP admissions. Whereas the mortality rate decreased overall (0.97%ue2320.83%, P<0.001), it remained unchanged in those with morbid obesity (1.02%ue2321.07%, P=1.0). Multivariate analysis revealed that morbid obesity was associated with increased mortality (odds ratio (OR) 1.6; 95% confidence interval (CI) 1.3, 1.9), prolonged hospitalization (0.4 days; P<0.001), and higher hospitalization charges (

Diagnosis of Exocrine Pancreatic Insufficiency

5,067; P<0.001). A propensity score-matched cohort analysis demonstrated that the primary outcomes, acute kidney failure (10.8 vs. 8.2%; P<0.001), respiratory failure (7.9 vs. 6.4%; P<0.001), and mortality (OR 1.6, 95% CI 1.2, 2.1) were more frequent in morbid obesity.CONCLUSIONS:Morbid obesity negatively influences inpatient hospitalization and is associated with adverse clinical outcomes, including mortality, organ failure, and health-care resource utilization. These observations and the increasing global prevalence of obesity justify ongoing efforts to understand the role of obesity-induced inflammation in the pathogenesis and management of AP.

Complications of Chronic Pancreatitis

Opinion statementThe accurate diagnosis of exocrine pancreatic insufficiency (EPI) helps identify those in need of pancreatic enzyme replacement therapy. Conversely, ruling out EPI identifies those in which additional evaluation should be pursued to explain their symptoms. There are many available tests that can be used to diagnose EPI; however, the tests must be tailored to each clinical scenario. Tests that are convenient but less accurate (e.g., fecal elastase-1, qualitative fecal fat determination) are best suited for patients with a high pretest probability of EPI. In contrast, tests that are highly accurate but more cumbersome (e.g., endoscopic pancreatic function testing, 72-h fecal fat collection) are favored in patients suspected to have mild EPI or an early stage of chronic pancreatitis. Additional research is needed to identify a more convenient means of accurately diagnosing at all stages of EPI.

Validation of diagnostic characteristics of needle based confocal laser endomicroscopy in differentiation of pancreatic cystic lesions

Chronic pancreatitis is a disease that leads to irreversible changes in the pancreatic morphology and function. The loss of function can lead to diabetes mellitus and exocrine pancreatic insufficiency. The inflammation and fibrosis can also lead to other complications including a chronic abdominal pain syndrome, metabolic bone disease, and pancretic cancer. This article reviews our current understanding of the mechanisms and management of these complications of chronic pancreatitis.

Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo.

Background and aims: Endoscopic ultrasound (EUS)-guided needle-based Confocal Laser Endomicroscopy (nCLE) characteristics of pancreatic cystic lesions (PCLs) have been identified in studies where the gold standard surgical histopathology was available in a minority of patients. There are diverging reports of interobserver agreement (IOA) and paucity of intraobserver reliability (IOR). Thus, we sought to validate current EUS-nCLE criteria of PCLs in a larger consecutive series of surgical patients. Methods: A retrospective analysis of patients who underwent EUS-nCLE at a single center was performed. For calculation of IOA (Fleiss’ kappa) and IOR (Cohen’s kappa), blinded nCLE-naïve observers (nu200a=u200a6) reviewed nCLE videos of PCLs in two phases separated by a 2-week washout period. Results: EUS-nCLE was performed in 49 subjects, and a definitive diagnosis was available in 26 patients. The overall sensitivity, specificity, and accuracy for diagnosing a mucinous PCL were 94u200a%, 82u200a%, and 89u200a%, respectively. The IOA for differentiating mucinous vs. non-mucinous PCL was “substantial” (κu200a=u200a0.67, 95u200a%CI 0.57, 0.77). The mean (± standard deviation) IOR was “substantial” (κu200a=u200a0.78u200a±u200a0.13) for diagnosing mucinous PCLs. Both the IOAs and mean IORs were “substantial” for detection of known nCLE image patterns of papillae/epithelial bands of mucinous PCLs (IOA κu200a=u200a0.63; IOR κu200a=u200a0.76u200a±u200a0.11), bright particles on a dark background of pseudocysts (IOA κu200a=u200a0.71; IOR κu200a=u200a0.78u200a±u200a0.12), and fern-pattern or superficial vascular network of serous cystadenomas (IOA κu200a=u200a0.62; IOR κu200a=u200a0.68u200a±u200a0.20). Three (6.1u200a% of 49) patients developed post-fine needle aspiration (FNA) pancreatitis. Conclusion: Characteristic EUS-nCLE patterns can be consistently identified and improve the diagnostic accuracy of PCLs. These results support further investigations to optimize EUS-nCLE while minimizing adverse events. Study registration: NCT02516488

Needle-based confocal laser endomicroscopy for the diagnosis of pancreatic cystic lesions: an international external interobserver and intraobserver study (with videos)

Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators of inflammatory and fibrotic processes during CP. Here, we utilized primary and immortalized PSC obtained from mice and patients with CP or pancreatic cancer to examine the effect of Jak/STAT and MAPK pathway inhibition in vitro. The well-characterized caerulein model of CP was used to assess the therapeutic efficacy of Jak1/2 inhibition in vivo. Treatment of cultured PSC with the Jak1/2 inhibitor ruxolitinib reduced STAT3 phosphorylation, cell proliferation, and expression of alpha-smooth muscle actin (α-SMA), a marker of PSC activation. Treatment with the MAPK inhibitor, MEK162, had less consistent effects on PSC proliferation and no impact on activation. In the caerulein-induced murine model of CP, administration of ruxolitinib for one week significantly reduced biomarkers of inflammation and fibrosis. These data suggest that the Jak/STAT pathway plays a prominent role in PSC proliferation and activation. In vivo treatment with the Jak1/2 inhibitor ruxolitinib reduced the severity of experimental CP, suggesting that targeting Jak/STAT signaling may represent a promising therapeutic strategy for CP.

Endoscopic Pancreas Fluid Collection: Methods and Relevance for Clinical Care and Translational Science

BACKGROUND AND AIMSnEUS-guided needle-based confocal laser endomicroscopy (nCLE) characteristics of common types of pancreatic cystic lesions (PCLs) have been identified; however, surgical histopathology was available in a minority of cases. We sought to assess the performance characteristics of EUS nCLE for differentiating mucinous from non-mucinous PCLs in a larger series of patients with a definitive diagnosis.nnnMETHODSnSix endosonographers (nCLE experience >30 cases each) blinded to all clinical data, reviewed nCLE images of PCLs from 29 patients with surgical (nxa0= 23) or clinical (nxa0= 6) correlation. After 2 weeks, the assessors reviewed the same images in a different sequence. A tutorial on available and novel nCLE image patterns was provided before each review. The performance characteristics of nCLE and the κ statistic for interobserver agreement (IOA, 95% confidence interval [CI]), and intraobserver reliability (IOR, mean ± standard deviation [SD]) for identification of nCLE image patterns were calculated. Landis and Koch interpretation of κ values was used.nnnRESULTSnA total of 29 (16 mucinous PCLs, 13 non-mucinous PCLs) nCLE patient videos were reviewed. The overall sensitivity, specificity, and accuracy for the diagnosis of mucinous PCLs were 95%, 94%, and 95%, respectively. The IOA and IOR (mean ± SD) were κxa0= 0.81 (almost perfect); 95% CI, 0.71-0.90; and κxa0= 0.86 ± 0.11 (almost perfect), respectively. The overall specificity, sensitivity, and accuracy for the diagnosis of serous cystadenomas (SCAs) were 99%, 98%, and 98%, respectively. The IOA and IOR (mean ± SD) for recognizing the characteristic image pattern of SCA were κxa0= 0.83 (almost perfect); 95% CI, 0.73-0.92; and κxa0= 0.85 ± 0.11 (almost perfect), respectively.nnnCONCLUSIONSnEUS-guided nCLE can provide virtual histology of PCLs with a high degree of accuracy and inter- and intraobserver agreement in differentiating mucinous versus non-mucinous PCLs. These preliminary results support larger multicenter studies to evaluate EUS nCLE. (Clinical trial registration number: NCT02516488.).