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Identifying endotypes of individuals after an attack of pancreatitis based on unsupervised machine learning of multiplex cytokine profiles

      Abstract

      After an attack of pancreatitis, individuals may develop metabolic sequelae (eg, new-onset diabetes) and/or pancreatic cancer. These new-onset morbidities are, at least in part, driven by low-grade inflammation. The aim was to study the profiles of cytokines/chemokines in individuals after an attack of pancreatitis. A commercially available panel including 31 cytokines/chemokines was investigated. Random forest classifier and unsupervised hierarchical clustering were applied to study participants (who had no persistent organ failure and did not require ICU admission) according to their cytokine/chemokine profiles. Pancreatitis-related characteristics, detailed body composition (determined using 3.0 T magnetic resonance imaging), markers of glucose, lipid, and iron metabolism, gut and pancreatic hormones, as well as liver and pancreatic enzymes, were compared between clusters. Bootstrap validation was employed. A total of 160 participants, including 107 postpancreatitis individuals (investigated at a median of 18 months after the last attack of pancreatitis) and 53 healthy volunteers, were studied. Twenty-two cytokines/chemokines were significantly different between postpancreatitis and health. Two distinct endotypes of individuals after an attack of pancreatitis were identified–‟inflammatory” and ‟noninflammatory.” Sixteen cytokines/chemokines were significantly higher in the inflammatory endotype compared with the noninflammatory endotype. No cytokine/chemokine was significantly higher in the noninflammatory endotype. The inflammatory endotype was characterized by significantly elevated insulin (P= 0.001), glucose-dependent insulinotropic peptide (P = 0.001), peptide YY (P = 0.017), and ghrelin (P = 0.014). The noninflammatory endotype was characterized by significantly elevated hepcidin (P= 0.016). Pancreatitis-related factors, body composition, and other studied parameters did not differ significantly between the 2 endotypes. Individuals with a similar phenotype and clinical course of pancreatitis have differing cytokine/chemokine profiles after clinical resolution of the disease. People with the inflammatory endotype have distinct changes in the pancreatic and gut hormones known to be involved in the pathogenesis of new-onset morbidities after an attack of pancreatitis.

      Abbreviations:

      ARIES (Analytic moRphomics In pancrEatic diseaSes), BMI (Body mass index), COSMOS (Clinical and epidemiOlogical inveStigations in Metabolism, nutritiOn, and pancreatic diseaseS), GIP (Glucose dependent insulinotropic peptide), GLP-1 (Glucagon-like peptide 1), HbA1c (Glycated hemoglobin), HDL (High density lipoprotein), HOMA-β (Homeostasis model of assessment of β cell function), HOMA-IR (Homeostasis model assessment of insulin resistance), ICU (Intensive care unit), IHFD (Intra-hepatic fat deposition), LDL (Low density lipoprotein), ROC (Receiver operation curve), SMFD (Skeletal muscle fat deposition)
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