Central role of the sentinel acute pancreatitis event (SAPE) model in understanding recurrent acute pancreatitis (RAP): Implications for precision medicine

Abstract

Traditional approaches to understanding the origins of chronic pancreatitis (CP) and find treatments led to abysmal failure. Thus, no drugs now exists to meet this need. Outdated concepts of the etiopathogenesis of CP have been replaced with new insights and disease models that provide the framework for early detection of the pathogenic pancreatitis process. Application of these principals require a new paradigm in disease definition and management, i.e. personalized / precision medicine. The key is acute pancreatitis (AP) starting with the first (sentinel) acute pancreatitis (AP) event (SAPE). This event sensitizes the pancreas to recurrent acute pancreatitis (RAP) as ongoing stressors drive various inflammatory responses to cause CP. The problem is the complex etiologies of AP and the additional genetic and environmental factors that promote progression to RAP and CP. This paper provides a background on the key conceptual changes that facilitate new approaches and the rationale for using mechanism-specific therapies to prevent RAP and CP.

Keywords: CFTR (cystic fibrosis transmembrane conductance regulator); CFTR-related disorders (CFTR-RD); alcohol; chronic pancreatitis in children; genetics; precision medicine; recurrent acute pancreatitis; smoking.

Figure 1

(A–E) Progressive CP pathogenesis. Five progressive stages can be defined that persist for days to many years. Each stage may have unique risk factors or stress/injury mechanisms, as well as innate compensatory or protective mechanisms that may be altered or defective in patients who progress. Stage B is a critical driver of the CP pathways as the initial episode of AP (SAPE) lowers the threshold for RAP. CP, chronic pancreatitis; DM, diabetes mellitus; RAP, recurrent acute pancreatitis; SAPE, sentinel acute pancreatitis event; PDAC, pancreatic ductal adenocarcinoma; T2, type II DM; T3c, type IIIc diabetes caused by exocrine pancreas pathology or surgery.