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Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial (NCT03452228) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (n = 19). Fifty-one patients (males, n = 27; females, n = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg−1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of −27.1% (37.4) (95% confidence interval −71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228.

OBJECTIVE Diabetes that arises from chronic pancreatitis (CP) is associated with increased morbidity and mortality. Methods to predict which patients with CP are at greatest risk for diabetes are urgently needed. We aimed to examine independent risk factors for diabetes in a large cohort of patients with CP. RESEARCH DESIGN AND METHODS This cross-sectional study comprised 645 individuals with CP enrolled in the PROCEED study, of whom 276 had diabetes. We conducted univariable and multivariable regression analyses of potential risk factors for diabetes. Model performance was assessed by area under the receiver operating characteristic curve (AUROC) analysis, and accuracy was evaluated by cross validation. Exploratory analyses were stratified according to the timing of development of diabetes relative to the diagnosis of pancreatitis. RESULTS Independent correlates of diabetes in CP included risk factors for type 2 diabetes (older age, overweight/obese status, male sex, non-White race, tobacco use) as well as pancreatic disease–related factors (history of acute pancreatitis complications, nonalcoholic etiology of CP, exocrine pancreatic dysfunction, pancreatic calcification, pancreatic atrophy) (AUROC 0.745). Type 2 diabetes risk factors were predominant for diabetes occurring before pancreatitis, and pancreatic disease–related factors were predominant for diabetes occurring after pancreatitis. CONCLUSIONS Multiple factors are associated with diabetes in CP, including canonical risk factors for type 2 diabetes and features associated with pancreatitis severity. This study lays the groundwork for the future development of models integrating clinical and nonclinical data to identify patients with CP at risk for diabetes and identifies modifiable risk factors (obesity, smoking) on which to focus for diabetes prevention.

Recurrent acute pancreatitis and chronic pancreatitis represent high morbidity diseases, which are frequently associated with chronic abdominal pain, pancreatic insufficiencies, and reduced quality of life. Currently, there are no therapies to reverse or delay disease progression, and clinical trials are needed to investigate potential interventions that would address this important gap. This conference report provides details regarding information shared during a National Institute of Diabetes and Digestive and Kidney Diseases-sponsored workshop on Clinical Trials in Pancreatitis that sought to clearly delineate the current gaps and opportunities related to the design and conduct of patient-focused trials in recurrent acute pancreatitis and chronic pancreatitis. Key stakeholders including representatives from patient advocacy organizations, physician investigators (including clinical trialists), the US Food and Drug Administration, and the National Institutes of Health convened to discuss challenges and opportunities with particular emphasis on lessons learned from trials in participants with other painful conditions, as well as the value of incorporating the patient perspective throughout all stages of trials.

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. METHODS: Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histological and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in two distinct human pancreatitis cohorts. RESULTS: Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss-of-ERRγ in primary acini abrogates mRNA expression and protein levels of mitochondrial oxidative phosphorylation (OXPHOS) complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, ER stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared to normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants (SNVs) for ERRγ that associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

In the article cited above, the affiliations for authors Stephen J. Pandol and Maike Sander were inadvertently transposed. The correct affiliation for Stephen J. Pandol is Department of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA. The correct affiliation for Maike Sander is Department of Pediatrics and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA. The online version of the article (https://doi.org/10.2337/db22-0942) has been updated with the correct affiliations.

CCR Translation for This Article from Serum Biomarker Panels for the Detection of Pancreatic Cancer

Purpose: Serum–biomarker based screening for pancreatic cancer could greatly improve survival in appropriately targeted high-risk populations.Experimental Design: Eighty-three circulating proteins were analyzed in sera of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC, n = 333), benign pancreatic conditions (n = 144), and healthy control individuals (n = 227). Samples from each group were split randomly into training and blinded validation sets prior to analysis. A Metropolis algorithm with Monte Carlo simulation (MMC) was used to identify discriminatory biomarker panels in the training set. Identified panels were evaluated in the validation set and in patients diagnosed with colon (n = 33), lung (n = 62), and breast (n = 108) cancers.Results: Several robust profiles of protein alterations were present in sera of PDAC patients compared to the Healthy and Benign groups. In the training set (n = 160 PDAC, 74 Benign, 107 Healthy), the panel of CA 19–9, ICAM-1, and OPG discriminated PDAC patients from Healthy controls with a sensitivity/specificity (SN/SP) of 88/90%, while the panel of CA 19–9, CEA, and TIMP-1 discriminated PDAC patients from Benign subjects with an SN/SP of 76/90%. In an independent validation set (n = 173 PDAC, 70 Benign, 120 Healthy), the panel of CA 19–9, ICAM-1 and OPG demonstrated an SN/SP of 78/94% while the panel of CA19–9, CEA, and TIMP-1 demonstrated an SN/SP of 71/89%. The CA19–9, ICAM-1, OPG panel is selective for PDAC and does not recognize breast (SP = 100%), lung (SP = 97%), or colon (SP = 97%) cancer.Conclusions: The PDAC-specific biomarker panels identified in this investigation warrant additional clinical validation to determine their role in screening targeted high-risk populations. Clin Cancer Res; 17(4); 805–16. ©2010 AACR.

Supplementary Figures S1-S2; Supplementary Tables S1-S2.

IntroductionDespite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency.MethodsAn online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years.ResultsOverall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency.ConclusionThis survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence. Introduction: Despite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency. Methods: An online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years. Results: Overall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency. Conclusion: This survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence.

INTRODUCTION: The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort. METHODS: We evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP. RESULTS: There were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3–5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier. CONCLUSIONS: Nearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention.

Pain is the most distressing and disruptive feature of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) resulting in low quality of life (QOL) and disabilities. There is no single, characteristic pain pattern in patients with RAP and CP. Abdominal imaging features of CP accurately reflect morphologic features but they do not correlate with pain. Pain is the major driver of poor quality of life (QOL) and it is the constant pain, rather than intermittent pain that drives poor QOL. Furthermore, the most severe constant pain experience in CP is also a complex condition. The ability to target the etiopathogenesis of severe pain requires new methods to detect the exact pain mechanisms in an individual at cellular, tissue, system and psychiatric levels. In patients with complex and severe disease, it is likely that multiple overlapping mechanisms are simultaneously driving pain, anxiety and depression. Quantitative sensory testing (QST) shows promise in detecting alterations in central processing of pain signals and to classify patients for mechanistic and therapeutic studies. New genetic research suggests that genetic loci for severe pain in CP overlap with genetic loci for depression and other psychiatric disorders, providing additional insights and therapeutic targets for individual patients with severe CP pain. Well-designed clinical trials that integrate clinical features, QST, genetics and psychological assessments with targeted treatment and assessment of responses are required for a quantum leap forward. A better understanding of the context and mechanisms contributing to severe pain experiences in individual patients is predicted to lead to better therapies and quality of life.

Poor translatability of animal disease models has hampered the development of new inflammatory bowel disorder (IBD) therapeutics. We describe a preclinical, ex vivo system using freshly obtained and well-characterized human colorectal tissue from patients with ulcerative colitis (UC) and healthy control (HC) participants to test potential therapeutics for efficacy and target engagement, using the JAK/STAT inhibitor tofacitinib (TOFA) as a model therapeutic. Colorectal biopsies from HC participants and patients with UC were cultured and stimulated with multiple mitogens ± TOFA. Soluble biomarkers were detected using a 29-analyte multiplex ELISA. Target engagement in CD3(+)CD4(+) and CD3(+)CD8(+) T-cells was determined by flow cytometry in peripheral blood mononuclear cells (PBMCs) and isolated mucosal mononuclear cells (MMCs) following the activation of STAT1/3 phosphorylation. Data were analyzed using linear mixed-effects modeling, t test, and analysis of variance. Biomarker selection was performed using penalized and Bayesian logistic regression modeling, with results visualized using uniform manifold approximation and projection. Under baseline conditions, 27 of 29 biomarkers from patients with UC were increased versus HC participants. Explant stimulation increased biomarker release magnitude, expanding the dynamic range for efficacy and target engagement studies. Logistic regression analyses identified the most representative UC baseline and stimulated biomarkers. TOFA inhibited biomarkers dependent on JAK/STAT signaling. STAT1/3 phosphorylation in T-cells revealed compartmental differences between PBMCs and MMCs. Immunogen stimulation increases biomarker release in similar patterns for HC participants and patients with UC, while enhancing the dynamic range for pharmacological effects. This work demonstrates the power of ex vivo human colorectal tissue as preclinical tools for evaluating target engagement and downstream effects of new IBD therapeutic agents. NEW & NOTEWORTHY Using colorectal biopsy material from healthy volunteers and patients with clinically defined IBD supports translational research by informing the evaluation of therapeutic efficacy and target engagement for the development of new therapeutic entities. Combining experimental readouts from intact and dissociated tissue enhances our understanding of the tissue-resident immune system that contribute to disease pathology. Bayesian logistic regression modeling is an effective tool for predicting ex vivo explant biomarker release patterns.

Background & Aims Idiopathic chronic pancreatitis (ICP) is the second most common subtype of CP. In 1994, researchers reported the bimodal age at onset of ICP symptoms: early onset ICP (EO-ICP; median age, 19.2 y) and late-onset ICP (LO-ICP; median age, 56.2 y). Ages of onset and clinical features of ICP differed from those of alcohol-related CP (ACP). However, variants in PRSS1 had not yet been associated with ICP. We reexamined ages of onset of ICP in a large, North American cohort of patients, and investigated the effects of genetic factors and alcohol use in patients with EO-ICP, LO-ICP, and ACP. Methods We performed a cross-sectional analysis of patients with CP of European ancestry enrolled in the North American Pancreatitis Study 2, a prospective study of 1195 patients with CP from 26 centers in the United States from August 2000 through December 2014. We compared age at onset of symptoms for 130 patients with CP who were lifetime abstainers from alcohol (61 patients with early onset and 69 patients with late onset), 308 light to moderate alcohol drinkers with CP, and 225 patients with ACP and heavy to very heavy alcohol use. DNA from available patients was analyzed for variants associated with CP in SPINK1, CFTR, and CTRC. The Kruskal–Wallis test was used to compare continuous variables across groups and based on genetic variants. Results Median ages at onset of symptoms were 20 years for patients with EO-ICP and no alcohol use, 58 years for patients with LO-ICP and no alcohol use, 47 years for light to moderate alcohol drinkers with CP, and 44 years for patients with ACP. A higher proportion of patients with EO-ICP had constant pain (65%) than patients with LO-ICP (31%) (P = .04). A higher proportion of patients with ACP had pseudocysts (43%) than patients with EO-ICP (11%) (P = .001). A higher proportion of patients with EO-ICP had pathogenic variants in SPINK1, CFTR, or CTRC (49%) than patients with LO-ICP (23%), light to moderate alcohol drinking with CP (26%), or ACP (23%) (P = .001). Among patients with variants in SPINK1, those with EO-ICP had onset of symptoms at a median age of 12 years, and light to moderate alcohol drinkers with CP had an age at onset of 24 years. Among patients with variants in CFTR, light to moderate alcohol drinkers had an age at onset of symptoms of 41 years, but this variant did not affect age at onset of EO-ICP or ACP. Conclusions We confirmed previously reported ages at onset of symptoms for EO-ICP and LO-ICP in a North American cohort. We found differences in clinical features among patients with EO-ICP, LO-ICP, and ACP. Almost half of patients with EO-ICP have genetic variants associated with CP, compared with approximately one quarter of patients with LO-CP or ACP. Genetic variants affect ages at onset of symptoms in some groups.

BACKGROUND/OBJECTIVES: Black Americans are at increased risk of chronic pancreatitis (CP) compared to their White counterparts. We aimed to describe the race-specific smoking history and lifetime drinking in patients diagnosed with CP. METHODS: We analyzed data on 334 Black and White CP participants of the North American Pancreatitis Study 2 Continuation and Validation Study and Ancillary Study. Lifetime drinking history and lifetime smoking history were collected through in-person interviews. Intensity, frequency, duration and current status of drinking and smoking were compared between Black and White CP participants, stratified by physician-defined alcohol etiology. In addition, drinking levels at each successive decades in life (20s, 30s, 40s) were compared by race and graphically portrayed as heat diagrams. RESULTS: Among patients with alcoholic CP, current smoking levels were not different by race (67-70%), but a smaller proportion of Black patients reported having smoked 1 or more packs per day in the past (32%) as compared to White patients (58%, p

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. The model includes vascular, interstitial and “third-space” compartments with variable permeability of plasma proteins at the capillaries. Consented patients from University of Pittsburgh Medical Center Presbyterian Hospital were studied. Preadmission and daily hematocrit (HCT), blood urea nitrogen (BUN), creatine (Cr), albumin (Alb), and total protein (TP) were collected, and nonalbumin plasma protein (NAPP = TP minus the Alb) was calculated. Subjects served as their own controls for trajectory analysis. Of 57 SAP subjects, 18 developed MOF (5 died), and 39 were non-MOF (0 died). Compared with preadmission levels, admission HCT increased in MOF +5.00 [25%-75% interquartile range, IQR] versus non-MOF −0.10 [−1.55, 1.40] (P < 0.002) with HCT > +3 distinguishing MOF from non-MOF (odds ratio 17.7, P = 0.014). Preadmission Alb fell faster in MOF than non-MOF (P < 0.01). By day 2, TP and NAPP dropped in MOF but not non-MOF (P < 0.001). BUN and Cr levels increased in MOF (P = 0.001), but BUN-to-Cr ratios remained constant. Pancreatic necrosis was more common in MOF (56%) than non-MOF (23%). Changing capillary permeability to allow loss of NAPP in this model predicts loss of plasma oncotic pressure and reduced vascular volume, hypotension with prerenal azotemia and acute kidney dysfunction, pancreas necrosis, and pulmonary edema from capillary leak in the lung with acute respiratory distress syndrome. Sequential biomarker analysis in humans with or without MOF is consistent with this model. This study is registered on https://clinicaltrials.gov at NCT03075605. NEW & NOTEWORTHY Acute pancreatitis is a sudden inflammatory response to pancreatic injury that may spread to systemic inflammation, multiorgan failure, and death in some patients. With the use of the predictions of a new mechanistic model, we compared patients with severe acute pancreatitis with or without multiorgan failure. All biomarkers of capillary leak and clinical features of multiorgan failure were accurately predicted. This provides a new paradigm for understanding and developing new treatments for patients with severe acute pancreatitis.

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.To define the degree of correlation between low trypsinogen levels as a marker of acinar cell function and variable features of CP.Serum samples from previously ascertained and well phenotyped case and control subjects from the North American Pancreatitis Study II (NAPS2) were used to measure serum trypsinogen levels in a commercial laboratory. Control samples were used to define normal ranges and compared with levels in CP patients with defined features.A final cohort of 279 CP patients and 262 controls from the NAPS2 studies were evaluated. In controls trypsinogen had a mean of 34.96 ng/ml and SD = 11.99. Cut-off values for low trypsinogen ranged from20 to 10 ng/ml and very low trypsinogen at10 ng/ml. Compared to controls, CP was associated with very low trypsinogen levels (p 0.0001). Within CP, very low trypsinogen levels correlated with parenchymal loss (pancreatic surgery [p 0.05]; atrophy with calcifications, [p 0.001]), EPI (p 0.01, trend p 0.001) and diabetes (trend p 0.01) but not CT-based criteria for fibrosis (pancreatic duct dilation, irregularity, strictures).Very low serum trypsinogen levels correlate with measures of acinar cell loss including surgical resection, atrophic-calcific CP, diabetes and functional symptoms EPI but not duct morphology criteria. Serum trypsinogen levels correlate with decreased acinar cell function and therefore have biomarker utility clinical management.

Purpose of review We describe and contrast the strengths of precision medicine with Western medicine, and complex trait genetics with Mendelian genetics. Classic genetics focuses on highly penetrant pathogenic variants in a single gene believed to cause or confer a high risk for well-defined phenotypes. However, a minority of disorders have a single gene cause. Further, even individuals with identical Mendelian disease-associated genotypes may exhibit substantial phenotypic variability indicative of genetic and environmental modifiers. Still, most diseases are considered complex traits (or complex diseases). Recent findings New insights into the genetic underpinnings of complex traits provide opportunities for advances in diagnosis and management. Precision medicine provides the framework for integrating complex trait knowledge into clinical care through a sophisticated analysis pipeline. Multidimensional modeling of acquired diseases includes multiple genetic risks scattered over many genes and gene regulators that must be interpreted on the basis of functional evidence (e.g., genomics, transcriptomics) with structured models and expert systems; strengthened with machine learning and artificial intelligence. The choice of genotyping approaches (shotgun sequencing, single nucleotide polymorphism chips, targeted panels) is discussed. Summary The result of a good precision medicine tool is clinical-decision support and guidance to tackle complex disorders such as pancreatitis, diabetes, and pancreatic cancer oncogenesis.

Hereditary pancreatitis (HP), a highly penetrant (~80%) autosomal dominant disease associated with PRSS1 variants, causes acute pancreatitis in childhood and chronic pancreatitis by early adulthood. Other clinical features include pain, diabetes, and risk of pancreatic cancer. HP kindreds were prospectively recruited from 1995 to 2015. At enrollment, study participants completed medical and family history questionnaires, and provided samples for genotyping. Participants were recontacted between 2015 and 2017 and asked to complete a survey on concerns and experiences related to HP, PRSS1 testing, and genetic counseling. Data were analyzed with descriptive and thematic methods. Thirty-nine affected participants with HP and 21 unaffected family members completed the survey. Among unaffected family members, 'worry' and 'helplessness' were frequently described as the most difficult problem in their family because of HP, particularly with regard to pain. Three participants described the impact of drug addiction on their family. 'School or work limitations' was the leading financial concern, with 65.5% (36/55) rating it as 'moderately' or 'extremely important.' Unexpectedly, only 62% (21/34) of affected PRSS1 carriers believed the chance for a parent to pass HP to his or her children was 50%, whereas 18% (6/34) believed the chance was 100%. The impact of HP on individuals and families varied, which may reflect the highly unpredictable nature of HP severity and outcomes. Based on current and previously reported findings, an overview of important issues for genetic counselors to consider for counseling HP families is included.

Objective This exploratory study seeks to identify distinct circulating immune signatures among patients having recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and pancreatic adenocarcinoma (PDAC). Methods A retrospective analysis of human serum samples from collaborating institutions of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) was performed. Samples came from the North American Pancreatitis Studies 2 (NAPS2) cohort and the Pancreatic Adenocarcinoma Gene Environment Risk Study (PAGER) and were analyzed using a 62-plex Luminex assay in a blinded fashion. Group and pairwise comparisons were performed to identify unique immune signature panels and to calculate diagnostic utility using area under the curve analysis. Results A total of 179 patients’ samples were included: 41 controls, 40 CP, 78 PDAC and 20 RAP patients, of which 20 controls, 20 CP, and 58 PDAC patients had diabetes mellitus (DM). A unique immune signature panel could discriminate RAP, CP, and PDAC from controls with an AUC range from 0.77 to 0.86 (95% CI range: 0.64–0.94), RAP from CP, and CP from PDAC with an AUC of 0.77 (95% CI 0.64–0.90) and 0.76 (95% CI 0.67–0.86), respectively. Furthermore, an immune signature panel could also discriminate PDAC-DM from DM controls with an AUC of 0.96 (95% CI: 0.93–1.00) Conclusion This study identifies unique immune analytes that may serve as novel diagnostic and predictive non-invasive biomarkers of RAP, CP, and PDAC. Further validation is warranted in prospective cohorts as developed by the CPDPC.

Backgraoud & Aims Aberrant epithelial bicarbonate (HCO3−) secretion caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is associated with several diseases including cystic fibrosis and pancreatitis. Dynamically regulated ion channel activity and anion selectivity of CFTR by kinases sensitive to intracellular chloride concentration ([Cl−]i) play an important role in epithelial HCO3− secretion. However, the molecular mechanisms of how [Cl−]i-dependent mechanisms regulate CFTR are unknown. Methods We examined the mechanisms of the CFTR HCO3− channel regulation by [Cl−]i-sensitive kinases using an integrated electrophysiological, molecular, and computational approach including whole-cell, outside-out, and inside-out patch clamp recordings and molecular dissection of WNK1 and CFTR proteins. In addition, we analyzed the effects of pancreatitis-causing CFTR mutations on the WNK1-mediated regulation of CFTR. Results Among the WNK1, SPAK, and OSR1 kinases that constitute a [Cl−]i-sensitive kinase cascade, the expression of WNK1 alone was sufficient to increase the CFTR bicarbonate permeability (PHCO3/PCl) and conductance (GHCO3) in patch clamp recordings. Molecular dissection of the WNK1 domains revealed that the WNK1 kinase domain is responsible for CFTR PHCO3/PCl regulation by direct association with CFTR, while the surrounding N-terminal regions mediate the [Cl−]i-sensitivity of WNK1. Furthermore, the pancreatitis-causing R74Q and R75Q mutations in the elbow helix 1 of CFTR hampered WNK1-CFTR physical associations and reduced WNK1-mediated CFTR PHCO3/PCl regulation. Conclusion The CFTR HCO3− channel activity is regulated by [Cl−]i and a WNK1-dependent mechanism. Our results provide new insights into the regulation of the ion selectivity of CFTR and the pathogenesis of CFTR-related disorders., Graphical abstract

Objective No standardized system is currently used to report the presence or severity of parenchymal and ductal features of chronic pancreatitis (CP) on CT scan. We report a modification to the previously proposed Cambridge classification to serve this purpose. Methods Contrast-enhanced CT scans of 158 well-phenotyped patients with CP enrolled in the North American Pancreatitis Studies (NAPS2) during 2000–2014 from the University of Pittsburgh were retrospectively reviewed by a subspecialty trained abdominal radiologist. Presence and severity (score scale 0–4) of pancreatic duct (PD) dilation, obstruction and contour irregularity, pancreatic calcifications, atrophy and extent of pancreatic involvement were recorded to grade the morphological severity of CP and stratify patients into distinct morphologic patterns. Findings were also correlated with clinical features. Results Pancreatic atrophy, calcifications, PD dilation and PD irregularity were observed in 80%, 68%, 65%, 58% cases, respectively. An obstructive stone or PD stricture was present in 63%, and 86% had diffuse pancreatic involvement. Using these features, CP was noted to be moderate or severe in 61%, and classified morphologically as obstructive with/without calcifications, calcific but non-obstructive and non-calcific/non-obstructive in 65%, 20%, 15%, respectively. Functional abnormalities but not the presence of pain generally correlated with imaging findings. Conclusion A structured scoring system can provide qualitative and quantitative assessment of imaging findings in CP and an opportunity for adoption into clinical practice and research for initial evaluation and longitudinal follow-up. Our findings need validation in a prospective cohort before widespread adoption.

Pancreatogenic diabetes mellitus, also termed type 3c diabetes (T3cD), or glucose intolerance develops in 25%-75% of adults with chronic pancreatitis (CP). The primary pathophysiologic defect in T3cD is insulin deficiency, thought to result largely from "bystander" injury to the islets from fibrotic changes in the exocrine pancreas and cytokine-induced beta cell dysfunction from intrapancreatic inflammation.

Objectives Chronic pancreatitis (CP) is associated with debilitating refractory pain. Distinct subtypes of CP pain have been previously characterized based on severity (none, mild-moderate, severe) and temporal (none, intermittent, constant) nature of pain, but no mechanism-based tools are available to guide pain management. This exploratory study was designed to determine if potential pain biomarkers could be detected in patient serum and whether they associate with specific pain patterns. Methods Cytokines, chemokines, and peptides associated with nociception and pain were measured in legacy serum samples from CP patients (N = 99) enrolled in the North American Pancreatitis Studies. The unsupervised hierarchical cluster analysis was applied to cluster CP patients based on their biomarker profile. Classification and regression tree was used to assess whether these biomarkers can predict pain outcomes. Results The hierarchical cluster analysis revealed a subset of patients with predominantly constant, mild-moderate pain exhibited elevated interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP1) whereas patients with higher interleukin-4 (IL-4), interleukin-8 (IL-8) and calcitonin gene related peptide (CGRP) were more likely to have severe pain. Interestingly, analyses of each individual biomarker revealed that patients with constant pain had reduced circulating TNFα and fractalkine. Patients with severe pain exhibited a significant reduction in TNFα as well as trends towards lower levels of IL-6 and substance P. Discussion The observations from this study indicate that unique pain experiences within the chronic pancreatitis population can be associated with distinct biochemical signatures. These data indicate that further hypothesis-driven analyses combining biochemical measurements and detailed pain phenotyping could be used to develop precision approaches for pain management in patients with chronic pancreatitis.

Chronic pancreatitis (CP) is a complex inflammatory disorder with numerous associated genetic and environmental risk factors. The most distressing characteristic of CP is recalcitrant pain, often requiring surgical resection including total pancreatectomy with islet autotransplantation (TPIAT). We studied five consented subjects undergoing pancreatic resection and processed isolated cells for single-cell RNA sequencing (scRNA-Seq). Using high-dimensional transcriptomic cluster analysis, we identified 11 unique cell clusters in the pancreas tissue. These cell clusters include a cluster of undifferentiated/dedifferentiated cells and two unique clusters of acinar cells, one of which appears to be in a transitional stage. To determine the cellular response to protease inhibitor and stimulation, we treated aliquots of cells from one subject with a protease inhibitor cocktail with and without bethanechol (a muscarinic receptor agonist) at 100 and 400 µM and compared gene expression profiles. The protease inhibitors appeared to reduce cell stress. Pancreatic digestive enzymes and islet hormones were upregulated in both doses of bethanechol-treated cells compared with naïve cells. High-dose bethanechol appeared to be toxic and consistent with hyperstimulation. These studies demonstrate the feasibility of investigating human acinar cell physiology at the single-cell level and initial evidence that these cells retain responsiveness to agonist stimulation with predicted second messenger and transcriptomic responses. NEW & NOTEWORTHY We conducted single cell RNA sequencing on pancreas tissue from five individuals. We identified eleven unique cell clusters including a large population of dedifferentiated cells as well as two unique clusters of acinar cells, one of which appears to exist in a transitional state. We also examined the cellular response of pancreas tissue to stimulation and identified affected genes and pathways, including pancreatic digestive enzymes.

Pancreatitis is a complex syndrome that results from many etiologies. Large well-characterized cohorts are needed to further understand disease risk and prognosis.A pancreatitis cohort of more than 4,200 patients and 24,000 controls were identified in the UK BioBank (UKBB) consortium. A descriptive analysis was completed, comparing patients with acute (AP) and chronic pancreatitis (CP). The Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent, and severe pancreatitis and Obstructive checklist Version 2 classification was applied to patients with AP and CP and compared with the control population.CP prevalence in the UKBB is 163 per 100,000. AP incidence increased from 21.4/100,000 per year from 2001 to 2005 to 48.2/100,000 per year between 2016 and 2020. Gallstones and smoking were confirmed as key risk factors for AP and CP, respectively. Both populations carry multiple risk factors and a high burden of comorbidities, including benign and malignant neoplastic disorders.The UKBB serves as a rich cohort to evaluate pancreatitis. Disease burden of AP and CP was high in this population. The association of common risk factors identified in other cohort studies was confirmed in this study. Further analysis is needed to link genomic risks and biomarkers with disease features in this population.

Background: Nicotinamide phosphoribosyltransferase (NAMPT) is a protein that exhibits dual functionality – as an intracellular enzyme which regulates nicotinamide adenine dinucleotide metabolism and as an extracellular protein (eNAMPT) secreted into the blood and functions as a cytokine regulator of innate immunity by activating NF-κB via binding to Toll-Like receptor 4. In limited preclinical and clinical studies, eNAMPT was implicated in the pathobiology of acute respiratory distress syndrome (ARDS) suggesting that eNAMPT could be a potential diagnostic and prognostic biomarker. Our aim was to investigate the feasibility of circulating eNAMPT levels to serve as a biomarker in an expanded cohort of patients with ARDS and ARDS-predisposing conditions such as acute pancreatitis, sepsis, and trauma when compared to controls. Methods: 795 patients and 179 healthy controls were included in the discovery and validation cohorts. Plasma and serum eNAMPT levels were quantified using one of two complementary Enzyme-linked Immunosorbent Assays. After log base 2 variance stabilizing transformation of plasma/serum eNAMPT measurements, differences between healthy controls and each disease cohort were compared using linear regression or generalized estimating equation (GEE) model where applicable. Complementary analyses included sensitivity, specificity, positive predictive values, negative predictive values, and the area under the receiver operating curve. Results: Compared to controls, circulating eNAMPT levels were significantly higher in patients with acute pancreatitis, with sepsis, with trauma, and with ARDS (all pConclusions: Circulating eNAMPT levels are a potential novel diagnostic biomarker in the critically ill with acute pancreatitis, sepsis, trauma, and/or ARDS.

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. Eligible criteria were subjects with AP and SIRS within 72 hours of presentation and those without organ failure. Subjects were allocated in a 1:1 ratio to indomethacin or placebo using simple randomization. Both interventions were administered rectally every 8 hours for 6 doses and compared using both intention-to-treat and per-protocol analyses. RESULTS: A total of 42 subjects (mean age 52 years, 55% men) were randomized to indomethacin (n = 18) or placebo (n = 24). There was no significant difference between the indomethacin and placebo groups in the change of SIRS score, proportion of subjects with SIRS, and distribution of SIRS scores at 24, 48, and 72 hours from randomization. There were no significant differences in the change of C-reactive protein levels at 48 hours or clinical outcomes between both treatment groups. Indomethacin was as safe as placebo, with 2 adverse events occurring in the placebo and none in the indomethacin arm. DISCUSSION: Rectal indomethacin can be safely administered over 48 hours; however, it is not superior to placebo in reducing the SIRS or clinical progression in a high-risk population with AP (ClinicalTrials.gov: NCT02692391).

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. Here, we tested the hypothesis that genetic risk of the psychiatric conditions of anxiety and post-traumatic stress disorder (PTSD) is associated with pain in CP and RAP + CP subjects. METHODS: The study cohort included phenotyped and genotyped RAP and CP patients from the North American Pancreatitis Study II of European Ancestry. Candidate genetic association studies were based on the absence of pain vs pain that is constant, constant-severe, or severe. Twenty-eight candidate genetic loci for anxiety and PTSD risk were identified in the literature and were the focus of this study. RESULTS: We identified 24 significant pain-associated single nucleotide polymorphisms within 13 loci across the 3 pain patterns in CP and RAP + CP (P < 0.002). Thirteen anxiety or PTSD genes were within these pain loci indicating nonrandom associations (P < 4.885 × 10−23). CTNND2 was associated with all pain categories and all pancreatitis etiologies. Implicated systems include neuronal signaling (HTR2A, DRD3, NPY, and BDNF), hypothalamic-pituitary-adrenal axis (NR3C1 and FKBP5), and cell-cell interaction (CTNND2 and THBS2). DISCUSSION: A component of constant and severe pain in patients with RAP and CP is associated with genetic predisposition to anxiety and PTSD. Identification of patients at risk eligible for trials of targeted treatment as a component of a multidisciplinary pain management strategy should be formally evaluated.

Effective management of complex pancreatic diseases demands precision medicine. While this new approach is technically feasible, many barriers to implementation impede realization of its promised benefits. Barriers exist in the acquisition and utilization of high quality, accurate, specific and quantitative information from both the clinical records and basic sciences. Barriers exist in integrating various domains of knowledge. Barriers exist in translating new insights from the bench to the bedside. Logistical barriers prevent seamless connection and interpretation of the necessary data elements. Barriers also exist with acceptance and application of precision medicine by major institutions and payers. Overcome these barriers will require high-level planning, clarity of vision into short and long term steps, and the commitment of innovative leaders, representing all stakeholders, to work together to reach a common goal.

Aims Cumulative consumption of alcohol and variations of alcohol intake by age are unknown in chronic pancreatitis (CP) patients in North America. This study summarizes the lifetime drinking history (LDH) by physician attribution of alcohol etiology, smoking status and sex in persons with CP. Methods We analyzed data on 193 CP participants who completed the LDH questionnaire in the North American Pancreatitis Continuation and Validation Study (NAPS2-CV). We collected data on frequency of drinking and drinks per drinking day for each drinking phase of their lives. We examined differences in total number of alcoholic drinks and weight of ethanol consumed by physician’s assessment of CP etiology, sex and smoking status. We also compared intensity of drinking in 20, 30 and 40s by timing of CP diagnosis. Results Persons diagnosed with alcoholic CP consumed median of 34,488 drinks (interquartile range 18,240–75,024) prior to diagnosis of CP, which occurred earlier than in persons with CP of other etiology (47 vs. 52 years). Cumulative drinking was greater in male vs. female patients. Male CP patients with a diagnosis of CP before the age of 45 drank more intensely in their 20s as compared to those with later onset of disease. Current smoking was prevalent (67%) among those diagnosed with alcoholic CP. Twenty-eight percent of patients without physician attribution of alcohol etiology reported drinking heavily in the past. Conclusions Lifetime cumulative consumption of alcohol and prevalence of current smoking are high in persons diagnosed with alcoholic pancreatitis. Intense drinking in early years is associated with earlier manifestation of the disease.

Background Severe hypertriglyceridemia (sHTG) is a rare condition, complicated by episodes of acute pancreatitis (AP), which can cause pain and/or life-threatening multi-organ dysfunction. Currently, there are no disease-specific patient-reported outcome (PRO) measures evaluating symptoms or dietary impact for this condition. Objective The objective of this study was to explore patient-reported symptoms and impacts of sHTG and AP and develop new measures to capture the symptoms and dietary impacts of this condition using patient language. Methods In-depth, semi-structured concept elicitation interviews were conducted with 12 US-based participants to explore their experience and identify key symptoms and impact on dietary behavior, both during and between episodes of AP. Participants had a range of AP severity with a previous triglyceride reading > 1000 mg/dL, and at least one attack of AP within the last 12 months. Transcripts were coded using thematic analysis. Results Qualitative data analysis revealed the substantial burden of AP associated with sHTG. Participants reported experiencing symptoms, especially abdominal pain, both during and between attacks of AP, and discussed considerable diet changes to prevent or minimize future attacks. A conceptual model was refined, based on patient input, and reviewed by clinical experts to determine key concepts for inclusion within two PRO measures, one evaluating symptoms and another evaluating impact on dietary behavior. Items were drafted using patient-derived language. A 19-item symptoms measure [Hypertriglyceridemia and Acute Pancreatitis Symptom Scale (HAP-SS)] and a 6-item dietary impact measure (Hypertriglyceridemia and Acute Pancreatitis Dietary Behavior (HAP-DB) measure) were developed, both with a 24-h recall period. Conclusions The qualitative analysis confirmed the substantial burden of AP associated with sHTG. This research resulted in development of two disease-specific PRO measures for use during and between attacks of AP. These measures are being utilized in a clinical trial, which will confirm content, structure, and psychometric properties. Electronic supplementary material The online version of this article (10.1007/s41669-019-0155-y) contains supplementary material, which is available to authorized users.

Detailed recommendations and guidelines for acute pancreatitis (AP) management currently exist. However, quality indicators (QIs) are required to measure performance in health care. The goal of the Acute Pancreatitis Task Force on Quality was to formally develop QIs for the management of patients with known or suspected AP using a modified version of the RAND/UCLA Appropriateness Methodology.A multidisciplinary expert panel composed of physicians (gastroenterologists, hospitalists, and surgeons) who are acknowledged leaders in their specialties and who represent geographic and practice setting diversity was convened. A literature review was conducted, and a list of proposed QIs was developed. In 3 rounds, panelists reviewed literature, modified QIs, and rated them on the basis of scientific evidence, bias, interpretability, validity, necessity, and proposed performance targets.Supporting literature and a list of 71 proposed QIs across 10 AP domains (Diagnosis, Etiology, Initial Assessment and Risk Stratification, etc.) were sent to the expert panel to review and independently rate in round 1 (95% of panelists participated). Based on a round 2 face-to-face discussion of QIs (75% participation), 41 QIs were classified as valid. During round 3 (90% participation), panelists rated the 41 valid QIs for necessity and proposed performance thresholds. The final classification determined that 40 QIs were both valid and necessary.Hospitals and providers managing patients with known or suspected AP should ensure that patients receive high-quality care and desired outcomes according to current evidence-based best practices. This physician-led initiative formally developed 40 QIs and performance threshold targets for AP management. Validated QIs provide a dependable quantitative framework for health systems to monitor the quality of care provided to patients with known or suspected AP.

OBJECTIVES. Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intra-pancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase (CEL) emerged as a trypsin-independent risk gene. Here, we evaluated PNLIP encoding pancreatic lipase as a potential novel susceptibility gene for CP. METHODS. We analyzed all 13 PNLIP exons in 429 German non-alcoholic CP patients and in 600 German control subjects, in 632 patients and 957 controls from France, and in 223 patients and 1070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 CP patients and 1849 controls originating from Germany, USA and India. We assessed the cellular secretion, lipase activity and proteolytic stability of recombinant PNLIP variants. RESULTS. In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P=0.02, OR=5.7, 95% CI=1.1–38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) versus controls (1/957 [0.1%]) (P=0.04, OR=7.6, 95% CI=0.9–172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1163 cases (1.1%) and in 3/3000 controls (0.1%) (OR=11.3, 95% CI=3.0–49.9, P