Inflammation, insufficiency, and malignancy : clinical pathways and risks across the pancreatic disease continuum

Background Pancreatic diseases comprise a heterogeneous group of inflammatory, metabolic, and malignant conditions with substantial morbidity and mortality. Chronic pancreatitis (CP) leads to progressive and irreversible structural damage of the pancreas with subsequent loss of endocrine and exocrine function. Diabetes developing after pancreatic injury has recently emerged as a distinct metabolic entity with unique clinical characteristics. Alcohol-related liver disease (ALD) and pancreatic disease frequently coexist, yet their epidemiological relationship and shared vulnerability remain incompletely understood. Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, is commonly accompanied by malnutrition and pancreatic exocrine insufficiency, factors that may influence treatment tolerance and survival. Despite their clinical importance, key aspects of risk stratification, disease progression, and supportive management across these pancreatic conditions remain insufficiently defined. Aims The thesis seeks to (1) identify subgroups of chronic pancreatitis patients at elevated risk of pancreatic ductal adenocarcinoma (PDAC); (2) characterize post-pancreatitis diabetes mellitus (PPDM) as a distinct metabolic disorder; (3) determine the risk of acute pancreatitis in individuals with alcohol-related liver disease on a population level; and (4) assess whether pancreatic enzyme replacement therapy (PERT) is associated with improved short-term survival in pancreatic cancer. Methods Four retrospective observational studies were conducted using clinical cohorts from Karolinska University Hospital and nationwide Swedish registry data. Study I included a large single-centre cohort of patients with definite chronic pancreatitis defined according to the M-ANNHEIM criteria and followed longitudinally to assess PDAC incidence and characterize clinical phenotypes in which PDAC occurred more frequently. Study II examined patients with chronic pancreatitis and diabetes, distinguishing PPDM from pre-existing type 2 diabetes and estimating cumulative incidence using competing-risk models accounting for death. Study III was a nationwide population-based cohort study comparing the incidence and severity of acute pancreatitis in patients with alcohol-related liver disease and matched general population controls. Study IV used a matched case-control design to evaluate the association between PERT use and one-year mortality in patients with PDAC. Results In Study I, the risk of pancreatic ductal adenocarcinoma in chronic pancreatitis was increased but heterogeneously distributed across the cohort, with PDAC clustering in small subgroups defined by distinct metabolic and nutritional profiles, including patients with diabetes and preserved or elevated body mass index, as well as those with pancreatic exocrine insufficiency accompanied by low body mass index. This non-uniform risk distribution argues against universal surveillance and supports risk-stratified follow-up strategies targeting clinically identifiable high-risk phenotypes. Study II demonstrated that post-pancreatitis diabetes mellitus is a common and progressively accumulating complication of chronic pancreatitis, affecting nearly 40% of patients after 20 years of follow-up, and characterized by a higher risk of microvascular complications, more frequent need for insulin therapy, with pancreatic calcifications emerging as the strongest independent predictor. In Study III, alcohol-related liver disease was associated with a substantial pancreatic burden, including approximately nine-fold higher odds of prevalent pancreatitis and a six-fold higher incidence and hospitalization rate for acute pancreatitis compared with the general population. Overall, about 10% of patients with ALD had a history of pancreatitis or developed acute pancreatitis during follow-up, with continued alcohol consumption acting as the dominant risk modifier, highlighting the clinical relevance of systematic assessment of prior pancreatic injury in this population. Finally, Study IV found that pancreatic enzyme replacement therapy use was associated with lower one-year mortality in pancreatic ductal adenocarcinoma, including among patients receiving best supportive care, although causal inference is limited by the observational study design. Conclusions This thesis demonstrates that pancreatic disease represents a continuum of interrelated inflammatory, metabolic, and nutritional disorders rather than isolated clinical entities. Cancer risk in chronic pancreatitis is concentrated in specific subgroups, supporting risk-stratified surveillance approaches. PPDM is a frequent and distinct consequence of pancreatic injury that warrants improved recognition and tailored management. Alcohol-related liver disease identifies a population with heightened pancreatic vulnerability, emphasizing the pancreas as a key target of alcohol-related systemic toxicity. Finally, nutritional support with PERT may play an important role in pancreatic cancer care, highlighting the need for prospective studies to clarify its impact on survival. Collectively, these findings support more individualized monitoring, prevention, and supportive treatment strategies across the spectrum of pancreatic disease. List of scientific papers This thesis is based on the following papers which are referred to in the text by their Roman numerical. I. Risk of Developing Pancreatic Cancer in Patients with Chronic Pancreatitis. Vujasinovic M, Dugic A, Maisonneuve P, Aljic A, Berggren R, Panic N, Valente R, Pozzi Mucelli R, Waldthaler A, Ghorbani P, Kordes M, Hagstrom H, Lohr J-M. J Clin Med. 2020;9(11):3720. PMID: 33228173. https://doi.org/10.3390/jcm9113720 II. Post-pancreatitis diabetes mellitus is common in chronic pancreatitis and is associated with adverse outcomes. Dugic A, Hagström H, Dahlman I, Rutkowski W, Daou D, Kulinski P, Löhr J-M, Vujasinovic M. United European Gastroenterol J. 2023;11(1):79-91. PMID: 36454055. https://doi.org/10.1002/ueg2.12344 III. Six-fold increased risk of acute pancreatitis in alcohol-related liver disease compared to matched comparators: A population-based cohort study. Dugic A, Widman L, Lohr JM, Hagstrom H. J Intern Med. 2025;297(2):213-226. PMID: 39655576. https://doi.org/10.1111/joim.20026 IV. Association between pancreatic enzyme replacement therapy and mortality in pancreatic cancer: a matched case-control study. Dugic A, Hagström H, Palmer I, Nouri A, Torabzadeh Tari H, Schmaderer L, Gustafsson Liljefors M, Ghorbani P, Löhr J-M, Vujasinovic M. Pancreatology. https://doi.org/10.1016/j.pan.2025.12.008