Multiomic definition of generalizable endotypes in human acute pancreatitis

Abstract

30Acute pancreatitis (AP) is sudden onset pancreas inflammation that causes multiple organ dysfunction syndrome (MODS) and death in certain individuals who develop AP yet minimal systemic inflammation in others. Here, we show that this observed diversity in systemic response and outcome is accompagnied by diversity in molecular subtypes that can be identified using computational analysis of clinical and multiomic data. We integrated co-incident whole blood transcriptomic, plasma proteomic, and serum metabolomic data at serial time points from a cohort of patients presenting with AP and systematically evaluated four different metrics for patient similarity, using unbiased mathematical, biological and clinical measures of internal and external validity. Our results identify four distinct and stable AP endotypes that are characterized by pathway and biomarker combination stereotypes into hypermetabolic, hepatopancreaticobiliary, 40 catabolic and innate immune endotypes. The catabolic endotype in AP strikingly recapitulates a disease endotype previously reported in acute respiratory distress syndrome, a recognized complication of AP. Our findings demonstrate that clinically-relevant and generalizable endotypes exist in AP. words3 Main Acute pancreatitis (AP) is defined as acute inflammation of the pancreas gland 1 . AP has a 50 worldwide incidence of 34 per 100,000 person-years 2 , and is the commonest gastrointestinal cause for emergency hospital admission 3 . Inflammatory damage to pancreatic acinar cells initiates an inflammatory cascade mediated by damage-associated molecular patterns, alarmins, inflammatory cytokines, metabolites and other soluble and cellular mediators of inflammation that propagate inflammation locally in the pancreas, and cause extrapancreatic organ dysfunction in the lungs, kidney and liver and other body systems, together resulting in multiple organ dysfunction syndrome (MODS) 4,5 . MODS occurs in 1 in 4 individuals who develop AP and is accompanied by deregulation of cardiovascular, autonomic nervous and immune system homeostasis 6 , leading to death in one fifth of those with AP-MODS 7 . Despite this currently accepted unifying disease model, each person who develops AP has a severity pattern of systemic inflammation and MODS 60 that is unique and is not directly proportional to the amount of pancreas damage on radiological imaging 8,9 , and this individualized response determines the disease outcome. This personalized response to AP is further nuanced by the diversity of etiologies and initiating events in AP, that include choledocholithiasis, excess ingestion of alcohol, trauma, pancreatic manipulation at endoscopy, viral infections, certain venoms and specific prescription medicines 6 . Currently, the clinicopathological paradigm in AP is convergent, whereby diverse etiologies converge onto acinar cell damage, and the resulting systemic inflammatory response is stratified as mild, moderate or severe (Figure 1a). We propose an alternative model that describes illness trajectories in AP,...

Subphenotypes in critical care: translation into clinical practice

“…Neyton et al recently used unsupervised clustering of proteomic, transcriptomic, and metabolomic data to describe four subphenotypes of acute pancreatitis dubbed "hypermetabolic", "hepatopancreaticobiliary", "catabolic", and "innate immune". 64 The hypermetabolic subphenotype exhibited increased markers of glutathione synthesis, gastrointestinal metabolism of dopamine, the tricarboxylic acid cycle, and sphingolipid biosynthesis (e.g. g-glutamyl transferase 2 [GGT2], citrulline, and serine palmitoyltransferase subunit B [SPTSSB]); the hepatopancreaticobiliary subphenotype was associated with bilirubin glucuronidation and bile transporters; the catabolic subphenotype was associated with proteolysis and apoptosis; and the innate immune subphenotype was associated with complement regulation and immune cell adherence.…”

“…g-glutamyl transferase 2 [GGT2], citrulline, and serine palmitoyltransferase subunit B [SPTSSB]); the hepatopancreaticobiliary subphenotype was associated with bilirubin glucuronidation and bile transporters; the catabolic subphenotype was associated with proteolysis and apoptosis; and the innate immune subphenotype was associated with complement regulation and immune cell adherence. 64 Pancreatitis is a "late entry" to the field of critical care subphenotyping and while these results are interesting, they are based on small sample sizes and have not yet been subject to peer review. Whether or not these groupings are robust and clinically meaningful remains unanswered.…”

Sepsis Subclasses: A Framework for Development and Interpretation*

“…In a study by Xiao et al (28), different injury mechanisms, trauma, burns, and endotoxemia yielded similarities in gene-expression patterns. Additionally, subclasses in acute pancreatitis may show similarities to those with ARDS (29). It is, therefore, likely that at least some of the molecular subclasses in sepsis will reflect general features of the host response to critical systemic injury.…”

Characterizing preclinical sub‐phenotypic models of acute respiratory distress syndrome: An experimental ovine study

“…These subphenotypes have distinct outcomes and, in retrospective analysis, have been shown to respond differently to several interventions. Related sub-phenotypes have also been identified in other conditions causing critical illness (Neyton et al, 2019;Vranas et al, 2017). However, the predominant clustering method employed in clinical cohorts, finite mixture modelling, is restricted in its applicability to preclinical studies, which are typically constrained to relatively small sample sizes (Dziak et al, 2014).…”