Circulating immune signatures in chronic pancreatitis with and without preceding acute pancreatitis: A pilot study.

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.

Pancreatic atrophy and exocrine insufficiency associate with the presence of diabetes in chronic pancreatitis patients, but additional mediators are operative.

OBJECTIVES: Diabetes mellitus is a frequent complication of chronic pancreatitis (CP) and has traditionally been considered to develop as a consequence of pancreatic islet cell loss. However, additional mechanisms may be operative including accumulation of pancreatic fat and fibrosis. We used advanced magnetic resonance imaging (MRI) to study pancreatic morphology and exocrine function in a reference population and in CP patients with and without diabetes. METHODS: This was a cross-sectional mono centre study. All subjects underwent advanced MRI including assessment of pancreatic ductal parameters (Cambridge classification and main pancreatic duct diameter), parenchymal parameters (DIXON technique and diffusion weighted imaging as proxies for pancreatic fat content and fibrosis, as well as pancreatic volume segmentation). Pancreatic exocrine function was determined as duodenal secretion following secretin stimulation and by the faecal elastase test. RESULTS: The study included 76 patients with definite CP of whom 23 (30.1%) had diabetes and 23 sex- and age matched healthy volunteers. Compared to their non-diabetic counterparts, diabetic patients were characterised by a low pancreatic volume (20 vs. 36 ml; p = .02) and impaired pancreatic exocrine function (faecal elastase 19 vs. 48 µg/g; p = .008), while no difference between patients with and without diabetes were seen in relation to MRI derived proxies for fibrosis and pancreatic fat accumulation and pancreatic duct parameters. A large proportion of non-diabetic patients (49%) had similar morphological and functional characteristics as patients with diabetes. CONCLUSION: Pancreatic atrophy and exocrine insufficiency are present in most CP patients with diabetes, but additional mediators seem to be operative in post pancreatitis diabetes mellitus.

Circulating immune signatures across clinical stages of chronic pancreatitis: a pilot study.

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.