Browsing by Author "Yadav, Dhiraj"

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    A Reduced Pancreatic Polypeptide Response is Associated With New-onset Pancreatogenic Diabetes Versus Type 2 Diabetes
    (The Endocrine Society, 2023) Hart, Phil A.; Kudva, Yogish C.; Yadav, Dhiraj; Andersen, Dana K.; Li, Yisheng; Toledo, Frederico G. S.; Wang, Fuchenchu; Bellin, Melena D.; Bradley, David; Brand, Randall E.; Cusi, Kenneth; Fisher, William; Mather, Kieren; Park, Walter G.; Saeed, Zeb; Considine, Robert V.; Graham, Sarah C.; Rinaudo, Jo Ann; Serrano, Jose; Goodarzi, Mark O.; Medicine, School of Medicine
    Purpose: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM). Methods: Subjects with new-onset DM (<3 years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index. Results: The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and <0.01, respectively). The fold change in PP at 15 minutes following meal stimulation was significantly lower in the PDAC-DM (median, 1.869) and CP-DM (1.813) groups compared with T2DM (3.283; P < 0.01 for both comparisons). The area under the curve of PP concentration was significantly lower in both the PDAC-DM and CP-DM groups than in T2DM regardless of the interval used for calculation and remained significant after adjustments. Conclusions: Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases.
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    Acute pancreatitis precedes chronic pancreatitis in the majority of patients: Results from the NAPS2 consortium
    (Elsevier, 2022-12) Singh, Vikesh K.; Whitcomb, David C.; Banks, Peter A.; AlKaade, Samer; Anderson, Michelle A.; Amann, Stephen T.; Brand, Randall E.; Conwel, Darwin L.; Cote, Gregory A.; Gardner, Timothy B.; Gelrud, Andres; Guda, Nalini; Forsmark, Christopher E.; Lewis, Michele; Sherman, Stuart; Muniraj, Thiruvengadam; Romagnuolo, Joseph; Tan, Xiaoqing; Tang, Gong; Sandhu, Bimaljit S.; Slivka, Adam; Wilcox, C. Mel; Yadav, Dhiraj; Medicine, School of Medicine
    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.
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    Assessing the Pathophysiology of Hyperglycemia in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms (DREAM) Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC)
    (Wolters Kluwer, 2022) Dungan, Kathleen M.; Hart, Phil A.; Andersen, Dana K.; Basina, Marina; Chinchilli, Vernon M.; Danielson, Kirstie K.; Evans-Molina, Carmella; Goodarzi, Mark O.; Greenbaum, Carla J.; Kalyani, Rita R.; Laughlin, Maren R.; Pichardo-Lowden, Ariana; Pratley, Richard E.; Serrano, Jose; Sims, Emily K.; Speake, Cate; Yadav, Dhiraj; Bellin, Melena D.; Toledo, Frederico G. S.; Type 1 Diabetes in Acute Pancreatitis Consortium; Medicine, School of Medicine
    Objectives: The metabolic abnormalities that lead to diabetes mellitus (DM) following an episode of acute pancreatitis (AP) have not been extensively studied. This manuscript describes the objectives, hypotheses, and methods of mechanistic studies of glucose metabolism that comprise secondary outcomes of the Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) Study. Methods: Three months after an index episode of AP, participants without pre-existing DM will undergo baseline testing with an oral glucose tolerance test. Participants will be followed longitudinally in three sub-cohorts with distinct metabolic tests. In the first and largest subcohort, oral glucose tolerance tests will be repeated 12 months after AP and annually to assess changes in β-cell function, insulin secretion, and insulin sensitivity. In the second, mixed meal tolerance tests will be performed at 3 and 12 months, then annually, and following incident DM to assess incretin and pancreatic polypeptide responses. In the third, frequently-sampled intravenous glucose tolerance tests will be performed at 3 months and 12 months to assess the first-phase insulin response and more precisely measure β-cell function and insulin sensitivity. Conclusions: The DREAM study will comprehensively assess the metabolic and endocrine changes that precede and lead to the development of DM after AP.
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    Association of Chronic Pancreatitis Pain Features With Physical, Mental, and Social Health
    (Elsevier, 2023) Yadav, Dhiraj; Askew, Robert L.; Palermo, Tonya; Li, Liang; Andersen, Dana K.; Chen, Minxing; Fisher, William E.; Fogel, Evan L.; Forsmark, Christopher E.; Hart, Phil A.; Othman, Mohamed O.; Pandol, Stephen J.; Park, Walter G.; Topazian, Mark D.; Van Den Eeden, Stephen K.; Swaroop Vege, Santhi; Yang, Yunlong; Serrano, Jose; Conwell, Darwin L.; Consortium for the Study of Chronic Pancreatitis; Diabetes, and Pancreatic Cancer (CPDPC); Medicine, School of Medicine
    Background and aims: Pain is a cardinal symptom of chronic pancreatitis (CP). Using Patient-Reported Outcomes Measurement Information System (PROMIS) measures, we characterized physical and mental health and symptom profiles of a well-defined cohort of individuals with CP and compared them with control subjects. Among patients with CP, we also examined associations between pain (intensity, temporal nature) and PROMIS symptom profiles and the prevalence of clinically significant psychological comorbidities. Methods: We analyzed baseline data in 488 CP patients and 254 control subjects enrolled in PROCEED (Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies), an ongoing longitudinal cohort study. Participants completed the PROMIS-Global Health, which captures global physical and mental health, and the PROMIS-29 profile, which captures 7 symptom domains. Self-reported pain was categorized by severity (none, mild-moderate, severe) and temporal nature (none, intermittent, constant). Demographic and clinical data were obtained from the PROCEED database. Results: Pain was significantly associated with impairments in physical and mental health. Compared with participants with no pain, CP participants with severe pain (but not mild-moderate pain) had more decrements in each PROMIS domain in multivariable models (effect sizes, 2.54-7.03) and had a higher prevalence of clinically significant depression, anxiety, sleep disturbance, and physical disability (odds ratios, 2.11-4.74). Similar results were noted for constant pain (but not intermittent pain) for PROMIS domains (effect sizes, 4.08-10.37) and clinically significant depression, anxiety, sleep disturbance and physical disability (odds ratios, 2.80-5.38). Conclusions: Severe and constant pain are major drivers for poor psychological and physical health in CP. Systematic evaluation and management of psychiatric comorbidities and sleep disturbance should be incorporated into routine management of patients with CP.
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    Association of Serum Endocannabinoid Levels with Pancreatitis and Pancreatitis-Related Pain
    (Mary Ann Liebert, 2025) Goodman, Marc T.; Lombardi, Christina; Torrens, Alexa; Bresee, Catherine; Saloman, Jami L.; Li, Liang; Yang, Yunlong; Fisher, William E.; Fogel, Evan L.; Forsmark, Christopher E.; Conwell, Darwin L.; Hart, Phil A.; Park, Walter G.; Topazian, Mark; Vege, Santhi S.; Van Den Eeden, Stephen K.; Bellin, Melena D.; Andersen, Dana K.; Serrano, Jose; Yadav, Dhiraj; Pandol, Stephen J.; Piomelli, Daniele; Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC); Medicine, School of Medicine
    Background and Aims: This investigation examined the association of pancreatitis and pancreatitis-related pain with serum levels of two endocannabinoid molecules such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and two paracannabinoid molecules such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Methods: A case-control study was conducted within the Prospective Evaluation of Chronic Pancreatitis for Epidemiological and Translational Studies, including participants with no pancreas disease (N = 56), chronic abdominal pain of suspected pancreatic origin or indeterminate chronic pancreatitis (CP) (N = 22), acute pancreatitis (N = 33), recurrent acute pancreatitis (N = 57), and definite CP (N = 63). Results: Circulating AEA concentrations were higher in women than in men (p = 0.0499), and PEA concentrations were higher in obese participants than those who were underweight/normal or overweight (p = 0.003). Asymptomatic controls with no pancreatic disease had significantly (p = 0.03) lower concentrations of AEA compared with all disease groups combined. The highest concentrations of AEA were observed in participants with acute pancreatitis, followed by those with recurrent acute pancreatitis, chronic abdominal pain/indeterminant CP, and definite CP. Participants with pancreatitis reporting abdominal pain in the past year had significantly (p = 0.04) higher concentrations of AEA compared with asymptomatic controls. Levels of 2-AG were significantly lower (p = 0.02) among participants reporting abdominal pain in the past week, and pain intensity was inversely associated with concentrations of 2-AG and OEA. Conclusions: Endocannabinoid levels may be associated with stage of pancreatitis, perhaps through activation of the CB1 receptor. Validation of our findings would support the investigation of novel therapeutics, including cannabinoid receptor-1 antagonists, in this patient population.
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    Characterizing mechanism-based pain phenotypes in patients with chronic pancreatitis: a cross-sectional analysis of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies
    (Wolters Kluwer, 2023) Saloman, Jami L.; Conwell, Darwin L.; Fogel, Evan; Vege, Santhi Swaroop; Li, Liang; Li, Shuang; Andersen, Dana K.; Fisher, William E.; Forsmark, Christopher E.; Hart, Phil A.; Pandol, Stephen J.; Park, Walter G.; Evans Phillips, Anna; Topazian, Mark; Van Den Eeden, Stephen K.; Serrano, Jose; Yadav, Dhiraj; Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer; Medicine, School of Medicine
    Pain is common in chronic pancreatitis (CP) and profoundly reduces quality of life (QoL). Multiple underlying mechanisms contribute to a heterogenous pain experience and reduce efficacy of pain management. This study was designed to characterize the distribution of mechanism-based pain phenotypes in painful CP. The data analyzed were collected as part of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies, an NCI/NIDDK-funded longitudinal study of the natural history of CP. The PROspective Evaluation of Chronic pancreatitis for EpidEmiologic and translational stuDies includes patient-reported outcome (PRO) measures of pain, medication use, global health, and QoL. Of subjects (N = 681) with CP, 80% experienced abdominal pain within the year before enrollment. Subjects who experienced pain in the week before enrollment (N = 391) completed PROMIS Neuropathic and Nociceptive Pain Quality instruments which were then used to classify them by pain type: 40% had nociceptive, 5% had neuropathic-like, and 32% had both types of pain. The prevalence of having both types of pain was higher among women and subjects with diabetes mellitus, whereas nociceptive-only pain was more prevalent among men and those with pancreatic duct stricture. Other factors, including pain medication use and healthcare utilization, did not differ between groups based on pain type. Subjects in the Both group had significantly worse health and QoL scores relative to those with nociceptive-only pain, suggesting that using psychosocial pain surveys may be useful for understanding pain subtypes in patients with CP. Additional research is needed to identify biochemical and biophysical signatures that may associate with and predict responses to mechanism-specific interventions.
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    Chronic pancreatitis: Pediatric and adult cohorts show similarities in disease progress despite different risk factors
    (Lippincott, Williams & Wilkins, 2020-04) Schwarzenberg, Sarah J.; Uc, Aliye; Zimmerman, Bridget; Wilschanski, Michael; Wilcox, C. Mel; Whitcomb, David C.; Werlin, Steven L.; Troendle, David; Tang, Gong; Slivka, Adam; Singh, Vikesh K.; Sherman, Stuart; Shah, Uzma; Sandhu, Bimaljit S.; Romagnuolo, Joseph; Rhee, Sue; Pohl, John F.; Perito, Emily R.; Ooi, Chee Y.; Nathan, Jaimie D.; Muniraj, Thiruvengadam; Morinville, Veronique D.; McFerron, Brian; Mascarenhas, Maria; Maqbool, Asim; Liu, Quin; Lin, Tom K.; Lewis, Michele; Husain, Sohail Z.; Himes, Ryan; Heyman, Melvin B.; Guda, Nalini; Gonska, Tanja; Giefer, Matthew J.; Gelrud, Andres; Gariepy, Cheryl E.; Gardner, Timothy B.; Freedman, Steven D.; Forsmark, Christopher E.; Fishman, Douglas S.; Cote, Gregory A.; Conwell, Darwin; Brand, Randall E.; Bellin, Melena; Barth, Bradley; Banks, Peter A.; Anderson, Michelle A.; Amann, Stephen T.; Alkaade, Samer; Abu-El-Haija, Maisam; Abberbock, Judah N.; Lowe, Mark E.; Yadav, Dhiraj; Medicine, School of Medicine
    Objectives: To investigate the natural history of chronic pancreatitis (CP), patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared. Methods: Demographics, risk factors, disease duration, management and outcomes of 224 children and 1,063 adults were compared using appropriate statistical tests for categorical and continuous variables. Results: Alcohol was a risk in 53% of adults and 1% of children (p<0.0001); tobacco in 50% of adults and 7% of children (p<0.0001). Obstructive factors were more common in children (29% vs 19% in adults, p=0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, p=0.107). Diabetes was more common in adults than children (36% vs 4% respectively, p<0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared to INSPPIRE subjects. These two cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, p=0.011). Conclusions: Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.
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    Circulating immune signatures across clinical stages of chronic pancreatitis: a pilot study
    (Wolters Kluwer, 2024) Hagn-Meincke, Rasmus; Hart, Phil A.; Andersen, Dana K.; Vege, Santhi S.; Fogel, Evan L.; Serrano, Jose; Bellin, Melena D.; Topazian, Mark D.; Conwell, Darwin L.; Li, Liang; Van Den Eeden, Stephen K.; Drewes, Asbjørn M.; Pandol, Stephen J.; Forsmark, Chris E.; Fisher, William E.; Yadav, Dhiraj; Olesen, Søren S.; Park, Walter G.; Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC); Medicine, School of Medicine
    Objective: This pilot study seeks to identify serum immune signatures across clinical stages of patients with chronic pancreatitis (CP). Methods: We performed a cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies-study. CP subjects were categorised into three clinical stages based on the presence/absence of metabolic complications: (1) CP with no diabetes and exocrine pancreatic dysfunction (EPD), (2) CP with either diabetes or EPD, and (3) CP with diabetes and EPD. Blinded samples were analysed using an 80-plex Luminex assay of cytokines/chemokines/adhesion molecules. Group and pairwise comparisons were performed to characterise immune signatures across CP subgroups. Results: A total of 135 CP subjects (evenly distributed between clinical stages) and 50 controls were studied. Interleukin-6 (IL-6), interleukin-8 (IL-8), and soluble intercellular adhesion molecule 1 (sICAM-1) were significantly elevated in CP subjects compared to controls. The levels of IL-6 and IL-8 increased with advancing disease stages, with the highest levels observed in CP with diabetes and EPD (clinical stage 3). Furthermore, hepatocyte growth factor and macrophage-derived chemokine were significantly increased in clinical stage 3 compared to controls. Conclusion: Our study reveals a progressive elevation in pro-inflammatory cytokines and chemokines with advancing clinical stages of CP. These findings indicate potential targets for the development of disease-modifying interventions.
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    Circulating Immune Signatures in Chronic Pancreatitis with and without Preceding Acute Pancreatitis: A Pilot Study
    (Elsevier, 2024) Hagn-Meincke, Rasmus; Yadav, Dhiraj; Andersen, Dana K.; Vege, Santhi Swaroop; Fogel, Evan L.; Serrano, Jose; Bellin, Melena D.; Topazian, Mark D.; Conwell, Darwin L.; Li, Liang; Van Den Eeden, Stephen K.; Drewes, Asbjørn M.; Pandol, Stephen J.; Forsmark, Chris E.; Fisher, William E.; Hart, Phil A.; Olesen, Søren S.; Park, Walter G.; Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC); Medicine, School of Medicine
    Objective: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP). Methods: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups. Results: In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10. Conclusion: CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP.
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    Clinical Trials in Pancreatitis: Opportunities and Challenges in the Design and Conduct of Patient-Focused Clinical Trials in Recurrent Acute and Chronic Pancreatitis: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop
    (Wolters Kluwer, 2022) Hart, Phil A.; Andersen, Dana K.; Lyons, Erica; Cote, Gregory A.; Cruz-Monserrate, Zobeida; Dworkin, Robert H.; Elmunzer, B. Joseph; Fogel, Evan L.; Forsmark, Christopher E.; Gilron, Ian; Golden, Megan; Gozu, Aysegul; McNair, Lindsay; Pandol, Stephen J.; Perito, Emily R.; Evans Phillips, Anna; Rabbitts, Jennifer A.; Whitcomb, David C.; Windsor, John A.; Yadav, Dhiraj; Palermo, Tonya M.; Medicine, School of Medicine
    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.