Mapping the uncharted territory: Abdominal adiposity and intra-pancreatic fat deposition after acute pancreatitis

Abstract

Background. Abdominal fat distribution occurs in a depot-specific manner with varying degree of fat accumulation in each depot. With advanced imaging modalities, it is now possible to quantify different adiposity and ectopic fat phenotypes. The negative impact of abdominal adiposity is observed not only in metabolic disorders but also gastrointestinal diseases. Acute pancreatitis (AP) is an exemplar gastrointestinal disease in which excess abdominal fat has been linked with serious in-hospital outcomes. While the influence of abdominal fat during early stages of AP is well established, there is paucity of research on long-term outcomes. Specifically, studies investigating abdominal adiposity (and ectopic fat phenotypes) and associated complications after resolution of AP are lacking. Furthermore, the pathophysiological mechanisms and contributing factors underlying metabolic sequelae after AP (such as new-onset prediabetes and diabetes) are poorly understood. Studies undertaken as part of this thesis aimed to determine the prevalence of intra-pancreatic fat deposition (IPFD) and to investigate the inter-relationships between abdominal adiposity, ectopic fat phenotypes (in particular IPFD) and metabolic derangements by analysing insulin traits, cytokine profile, lipocalin proteins, and other biological markers. Methods. Three projects were conducted as part of this thesis. First, a cross-sectional project (DORADO), including 92 individuals after AP, investigated the associations between abdominal adiposity and insulin resistance (IR), pro-inflammatory cytokines, and lipocalin proteins. Second, two systematic reviews investigated the prevalence of fatty pancreas and its correlation with metabolic co-morbidities and common biological markers. Pooled prevalence analyses, relative risk, and correlations meta-analyses were conducted. Third, a cross-sectional magnetic resonance imaging (MRI) project (ARIES), including 90 individuals after AP and 34 healthy volunteers, investigated the associations between MRI-derived variables and insulin traits, pro-inflammatory cytokines, serum lipid profile, and lipocalin proteins. All ARIES participants underwent abdominal 3T MRI and intra-hepatic fat%, intra-pancreatic fat%, visceral fat volume (VFV), subcutaneous fat volume (SFV), and visceral-to-subcutaneous (V/S) fat volume ratio were quantified. Fasting venous blood was collected to measure fasting blood glucose (FBG) (enzymatic colourimetric assay), glycated haemoglobin (HbA1c) (boronate affinity chromatography assay), pro-inflammatory cytokines (interleukin (IL)-6, CC motif chemokine ligand 2 (CCL2), leptin, tumour necrosis factor (TNF)-α, adipokines (adiponectin, omentin, and vaspin), and lipocalin proteins (lipocalin (LCN)-2) and retinol binding protein (RBP)-4). The MILLIPLEX® MAP or ELISA techniques were used to measure all studied analytes. A series of linear regression, binary logistic regression, modified Poisson regression, using unadjusted and numerous adjusted models (accounting for metabolic-, patient- and pancreatitis-related risk factors), were conducted. Results. Findings from the three projects show that specific abdominal adiposity phenotypes (waist circumference (WC), VFV, V/S fat volume ratio) and ectopic fat phenotypes (IPFD) are significantly higher in individuals with diabetes after AP, in comparison with no diabetes after AP and healthy groups (p < 0.001 for WC, VFV, IPFD, p = 0.001 for V/S fat volume ratio); abdominal adiposity (as defined by WC) is associated with significantly increased IR, IL-6, TNFα, leptin, and LCN-2 in individuals after AP; the pooled prevalence of fatty pancreas (in the systematic review including 12,675 individuals) was 33% (95%CI, 24-41%); presence of fatty pancreas is associated with 2.08 (95%CI, 1.44-3.00; p < 0.01) times increased risk of diabetes, 2.37 (95%CI, 2.07-2.71; p < 0.01) times increased risk of metabolic syndrome; IPFD is inversely associated with insulin trait (Raynaud index) and oxyntomodulin; IPFD is associated with significantly increased levels of leptin, TNFα, triglycerides, and total cholesterol to HDL-C ratio, and LCN-2 in individuals after AP, whereas none of the other analytes are associated with IPFD in healthy individuals. Conclusion. Intra-pancreatic fat deposition is an important clinical entity. The results from this thesis show that abdominal adiposity and IPFD contribute to metabolic derangements after AP (diabetes, IR). The increased circulating levels of pro-inflammatory cytokines and their association with the studied phenotypes suggests that chronic low-grade inflammation is one of the key drivers of AP metabolic sequelae. Future well-designed longitudinal studies are now required to investigate the role of IPFD in chronic low-grade inflammation. The studied biomarkers of IPFD sets the stage for diagnostic accuracy studies to determine their predictive value beyond post-pancreatitis setting.