Acute pancreatitis: Translating early mechanisms to bedside management.

Abstract

Acute pancreatitis (AP) is a burgeoning challenge. The first week of the disease is generally considered early AP. Events that occur during this phase can determine the magnitude of subsequent events. Even after decades of research, there is still no curative therapy for early AP. One of the earliest events of clinical AP is the co-localization of zymogen and trypsinogen within autophagolysosome which is followed by trypsin activation. The resulting acinar injury releases damaged-associated molecular patterns (DAMPs) that trigger cytokine production by the resident immune cells. Concurrently, there will be neutrophil infiltration, endothelial dysfunction and capillary leak. The local intra-pancreatic inflammation will activate the circulating mononuclear cells traversing the inflamed pancreas and in turn, get activated and perpetuate the systemic inflammatory response syndrome (SIRS). This eventually triggers organ damage. Concurrently, another phenomenon called compensatory anti-inflammatory response syndrome (CARS) ensues, that makes the patient susceptible to infections including infected necrosis. CARS is characterized by the downregulation of human leukocyte antigen (HLA)-DR and results in immunosuppression. The intestine also has a substantial role in determining the severity progression of systemic events in AP. The three components of the intestine that have been implicated include gut mucosal barrier, the microbiota and intestinal lymph. Intestinal inflammation occurs as a part of SIRS and results in the loss of tight junctions and apoptosis of the intestinal epithelial cells thereby increasing the mucosal permeability. Meanwhile, there will be gut microbial dysbiosis resulting in the translocation of pathogens and pathogen-associated molecular patterns (PAMPS) into the circulation. This would result in infections, which was already facilitated by CARS. In addition, the intestinal lymph could also result in translocation of intestinal toxins to the systemic circulation thereby contributing to the severity of AP. This narrative review discusses the current understanding of the mechanisms of early AP and the clinical implications.