Genetics of constant and severe pain in the NAPS2 cohort of recurrent acute and chronic pancreatitis patients.

Recurrent acute and chronic pancreatitis (RAP, CP) are complex, progressive inflammatory diseases with variable pain experiences impacting patient function and quality of life. The genetic variants and pain pathways in patients contributing to most severe pain experiences are unknown. We used previously genotyped individuals with RAP/CP from the North American Pancreatitis Study II (NAPS2) of European Ancestry for nested genome-wide associated study (GWAS) for pain-severity, chronicity, or both.

The burden of recurrence acute pancreatitis and annual event rates are underestimated because of high rates of home self-management.

Background/objectives: The event-rate of recurrent acute pancreatitis (RAP) in patient populations is critical for powering research studies. We hypothesize that some patients manage RAP attacks at home, reducing event rate estimations based on counting emergency department (ED) visits and hospitalizations only. The aim of this study was to determine the rates of home self-management of recurrent acute pancreatitis compared to ED visits and hospitalizations.

Relationship of circulating levels of long-chain fatty acids to persistent organ failure in acute pancreatitis.

During acute pancreatitis (AP), free fatty acids (FFAs) are liberated from circulating triglycerides (TG) and injured adipocytes by pancreatic lipase. Circulating FFAs have been suspected as a source of systemic lipotoxicity in AP. However, assessment of FFAs is difficult and time-consuming, and little is known about relative levels of FFAs between patients with different severities of AP and controls.

Severe acute pancreatitis exhibits distinct cytokine signatures and trajectories in humans: a prospective observational study.

Severe acute pancreatitis (SAP) is associated with substantial morbidity and mortality. Several cytokines have been identified to have pathophysiological significance in SAP, but studies characterizing their early trajectories are lacking. Here we characterize the early trajectories of seven key cytokines associated with SAP and compare them with non-SAP subjects.

Circulating eNAMPT as a biomarker in the critically ill: acute pancreatitis, sepsis, trauma, and acute respiratory distress syndrome.

Background: Nicotinamide phosphoribosyltransferase (NAMPT) exhibits dual functionality - as an intracellular enzyme regulating nicotinamide adenine dinucleotide metabolism and as an extracellular secreted protein (eNAMPT) to function as a cytokine regulator of innate immunity via binding to Toll-Like receptor 4 and NF-κB activation. In limited preclinical and clinical studies, eNAMPT was implicated in the pathobiology of acute respiratory distress syndrome (ARDS) suggesting that eNAMPT could potentially serve as a diagnostic and prognostic biomarker. We investigated the feasibility of circulating eNAMPT levels to serve as a biomarker in an expanded cohort of patients with ARDS and ARDS-predisposing conditions that included acute pancreatitis, sepsis, and trauma with comparisons to controls.

Estrogen-Related Receptor γ Maintains Pancreatic Acinar Cell Function and Identity by Regulating Cellular Metabolism.

Background & Aims: Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production.

Acute and Chronic Pancreatitis Disease Prevalence, Classification, and Comorbidities: A Cohort Study of the UK BioBank.

Introduction: Pancreatitis is a complex syndrome that results from many etiologies. Large well-characterized cohorts are needed to further understand disease risk and prognosis.

Methods: A pancreatitis cohort of more than 4,200 patients and 24,000 controls were identified in the UK BioBank (UKBB) consortium.

Rectal Indomethacin Does Not Mitigate the Systemic Inflammatory Response Syndrome in Acute Pancreatitis: A Randomized Trial.

Introduction: Experimental data suggest that nonsteroidal antiinflammatory drugs may prevent disease severity and mortality in acute pancreatitis (AP). The aim of this study was to compare the efficacy of rectal indomethacin vs placebo in reducing the systemic inflammatory response syndrome (SIRS) score in a high-risk AP population for clinical progression.

Methods: We conducted a single-center, quadruple-blinded, randomized, placebo-controlled trial.

Pain Experience in Pancreatitis: Strong Association of Genetic Risk Loci for Anxiety and PTSD in Patients With Severe, Constant, and Constant-Severe Pain.

Introduction: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are progressive inflammatory syndromes with variable features. Pain is the primary feature that contributes to low physical and mental quality of life with a third of patients reporting severe pain. Pain experience is worsened by depression.

A Novel 5-Cytokine Panel Outperforms Conventional Predictive Markers of Persistent Organ Failure in Acute Pancreatitis.

Introduction: Existing laboratory markers and clinical scoring systems have shown suboptimal accuracies for early prediction of persistent organ failure (POF) in acute pancreatitis (AP). We used information theory and machine learning to select the best-performing panel of circulating cytokines for predicting POF early in the disease course and performed verification of the cytokine panel's prognostic accuracy in an independent AP cohort.

Methods: The derivation cohort included 60 subjects with AP with early serum samples collected between 2007 and 2010.

Dynamic changes in the pancreatitis activity scoring system during hospital course in a multicenter, prospective cohort.

Background And Aim: The primary aim was to validate the Pancreatitis Activity Scoring System (PASS) in a multicenter prospectively ascertained acute pancreatitis (AP) cohort. Second, we investigated the association of early PASS trajectories with disease severity and length of hospital stay (LOS).

Methods: Data were prospectively collected through the APPRENTICE consortium (2015-2018).

Assessment of Weight Loss and Gastrointestinal Symptoms Suggestive of Exocrine Pancreatic Dysfunction After Acute Pancreatitis.

Introduction: Studies evaluating the natural history of exocrine pancreatic dysfunction (EPD) after acute pancreatitis (AP) are sparse. This study aims to assess incidence and predictors of weight loss and gastrointestinal (GI) symptoms suggestive of EPD 12 months after an AP episode.

Methods: Patients enrolled in the Pancreatitis-associated Risk of Organ Failure Study at the time of an AP episode were included.

Low serum trypsinogen levels in chronic pancreatitis: Correlation with parenchymal loss, exocrine pancreatic insufficiency, and diabetes but not CT-based cambridge severity scores for fibrosis.

Background: Chronic pancreatitis (CP) is a complex inflammatory disorder of the pancreas affecting acinar cells, duct cells, islet cells and inflammatory cells including fibrosis-producing stellate cells. Serum trypsinogen is a biomarkers of acinar cell function.

Aim: To define the degree of correlation between low trypsinogen levels as a marker of acinar cell function and variable features of CP.

Severe acute pancreatitis: capillary permeability model linking systemic inflammation to multiorgan failure.

Severe acute pancreatitis (SAP) includes persistent systemic inflammation (SIRS) and multiorgan failure (MOF). The mechanism of transition from SIRS to MOF is unclear. We developed a fluid compartment model and used clinical data to test predictions.

Constant-severe pain in chronic pancreatitis is associated with genetic loci for major depression in the NAPS2 cohort.

Background: Pain is the most debilitating symptom of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) and often requires chronic opioids or total pancreatectomy with islet autotransplantation to manage. Pain is a complex experience that can be exacerbated by depression and vice versa. Our aim was to test the hypothesis that depression-associated genes are associated with a constant-severe pain experience in RAP/CP patients.

Genetic Risk Score in Diabetes Associated With Chronic Pancreatitis Versus Type 2 Diabetes Mellitus.

Introduction: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM.

Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts.

Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants and environmental factors may increase the risk of cancer and accelerate the oncogenic process. We systematically reviewed, annotated, and classified previously reported pancreatic cancer-associated germline variants in established risk genes.

Known genetic susceptibility factors for chronic pancreatitis in patients of European ancestry are rare in patients of African ancestry.

Background: Multiple pathogenic genetic variants are associated with pancreatitis in patients of European (EA) and Asian ancestries, but studies on patients of African ancestry (AA) are lacking. We evaluated the prevalence of known genetic variations in African-American subjects in the US.

Methods: We studied prospectively enrolled controls (n = 238) and patients with chronic (CP) (n = 232) or recurrent acute pancreatitis (RAP) (n = 45) in the NAPS2 studies from 2000-2014 of self-identified AA.

Clinical outcomes of isolated renal failure compared to other forms of organ failure in patients with severe acute pancreatitis.

Aim: To assess differences in clinical outcomes of isolated renal failure (RF) compared to other forms of organ failure (OF) in patients with severe acute pancreatitis (SAP).

Methods: Using a prospectively maintained database of patients with acute pancreatitis admitted to a tertiary medical center between 2003 and 2016, those with evidence of persistent OF were classified to renal, respiratory, cardiovascular, or multi-organ (2 or more organs). Data regarding demographics, comorbidities, etiology of acute pancreatitis, and clinical outcomes were prospectively recorded.

Acute pancreatitis patient registry to examine novel therapies in clinical experience (APPRENTICE): an international, multicenter consortium for the study of acute pancreatitis.

Background: We have established a multicenter international consortium to better understand the natural history of acute pancreatitis (AP) worldwide and to develop a platform for future randomized clinical trials.

Methods: The AP patient registry to examine novel therapies in clinical experience (APPRENTICE) was formed in July 2014. Detailed web-based questionnaires were then developed to prospectively capture information on demographics, etiology, pancreatitis history, comorbidities, risk factors, severity biomarkers, severity indices, health-care utilization, management strategies, and outcomes of AP patients.