A narrative review of acute pancreatitis and its diagnosis, pathogenetic mechanism, and management

Abstract

Acute pancreatitis (AP) is an inflammatory disease that can progress to severe acute pancreatitis (SAP), which increases the risk of death. AP is characterized by inappropriate activation of trypsinogen, infiltration of inflammatory cells, and destruction of secretory cells. Other contributing factors may include calcium (Ca²⁺) overload, mitochondrial dysfunction, impaired autophagy, and endoplasmic reticulum (ER) stress. In addition, exosomes are also associated with pathophysiological processes of many human diseases and may play a biological role in AP. However, the pathogenic mechanism has not been fully elucidated and needs to be further explored to inform treatment. Recently, the treatment guidelines have changed; minimally invasive therapy is advocated more as the core multidisciplinary participation and "step-up" approach. The surgical procedures have gradually changed from open surgery to minimally invasive surgery that primarily includes percutaneous catheter drainage (PCD), endoscopy, small incision surgery, and video-assisted surgery. The current guidelines for the management of AP have been updated and revised in many aspects. The type of fluid to be used, the timing, volume, and speed of administration for fluid resuscitation has been controversial. In addition, the timing and role of nutritional support and prophylactic antibiotic therapy, as well as the timing of the surgical or endoscopic intervention, and the management of complications still have many uncertainties that could negatively impact the prognosis and patients' quality of life. Consequently, to inform clinicians about optimal treatment, we aimed to review recent advances in the understanding of the pathogenesis of AP and its diagnosis and management.

Keywords: Acute pancreatitis (AP); complications; diagnostic criteria; management; pathogenetic mechanism; prognosis.

Figure 1

(a) Cholecystokinin, alcohol, and bile acids activate the ER to release stored Ca²⁺ via the InsP3 receptor pathway. ORAI1 promotes Ca²⁺ to enter the cell from the extracellular space, further increasing the Ca²⁺ overload. (b) Sustained Ca²⁺ overload increases the permeability of MPTP, which determines the sensitivity of cyclophilin D. (c) Change in the membrane potential, leading to ATP depletion and cell necrosis. (d) ATP depletion damages acinar cells by blocking SERCA and PMCA, which aggravates the intracellular Ca²⁺ overload. (e) Ca²⁺ overload can activate trypsinogen and inflammatory signaling pathways. (f) Ca²⁺ overload can also cause mitochondrial dysfunction, leading to impaired autophagy. ER, endoplasmic reticulum; Ca²⁺, calcium; MPTP, mitochondrial permeability transition pores; ATP, adenosine triphosphate; SERCA, smooth ER Ca²⁺ channels; PMCA, plasma membrane Ca²⁺ channels.

Figure 2

(a) Alcohol, bile acids, and pancreatic toxins stimulate acinar cells, increasing lysosome synthesis. (b) Pancreatic toxins inhibit the release of zymogen granules from the apex of acinar cells, which leads to an increase in the content of zymogen granules. (c) The lysosome and zymogen granules become fused, a process known as colocalization. (d) Cathepsin B causes trypsinogen activation, resulting in the release of cathepsin B and trypsin into the cytoplasm. The released cathepsin B acts on the RIP3-RIP1-MLKL signaling pathway to promote RIP3-RIP1 necrosis complex formation. (e) The RIP3-RIP1 complex acts on the MLKL, causing MLKL phosphorylation and oligomerization, which then translocates to the plasma membrane, ultimately leading to acinar cells necroptosis. (f) The cathepsin B released after lysosomal membrane rupture leads to the release of cytochrome-c from the mitochondria, which activates caspase-3 and mediates cell apoptosis.

Figure 3

(a) After being stimulated by autophagy signals, cells form a circular open double membrane from the ER, with the Golgi apparatus and plasma membrane, to form an autophagy precursor. These autophagy precursors elongate aged organelles. (b) Autophagy precursors gradually enclose aged organelles to form vesicle-like structures, subsequently developing into autophagosomes. (c) The autophagosomes transfer their encapsulated contents to the lysosome cavity and subsequently fuse with lysosomes, under the mediating influence of LAMP. (d) Aged organelles are degraded by lysosome hydrolase (cathepsin B), and the degradation products are recycled in the cell. ER, endoplasmic reticulum; LAMP, lysosomal associated membrane protein.

Figure 4

(a) ER stress can be triggered by alcohol, bile acids, pancreatic toxins, and increased protein synthesis. UPR is caused by an increase of misfolded or unfolded proteins in the ER. (b) ATF6 is transferred to the Golgi apparatus and is cleaved by S1P and S2P. The N-terminal transcription activation domain is released and transferred to the nucleus as a transcription factor to promote transcription of the target gene. (c) PERK-mediated phosphorylation of eIF2α shuts off mRNA translation, decreasing the protein folding load and preventing misfolded proteins from being accumulated. ATF4 upregulation can result in CHOP expression, inducing cell apoptosis. (d) When the IRE1 signaling pathway is activated, IRE1 excises a 26 nucleotide intron to form the XBP1s. The protein encoded by the XBP1 is rapidly degraded (ERAD), relieving ER stress. ER, endoplasmic reticulum; UPR, unfolded protein response; ATF, activating transcription factor; PERK, PRK-like ER kinase.

Figure 5

(a) During the AP, the pancreas can release the exosomes to peripheral blood, some of exosomes (green circle) can reach the liver via the portal system and can be retained in the liver tissue. (b) The remaining part of the exosomes (yellow circle) can be degraded by the high hydrolytic activity of the PAAF and then is transferred to the hepatic tissue (c) The liver generates and releases the new exosomes (blue circle) to the circulatory system. (d) The new exosomes (blue circle) reach alveolar tissues and are absorbed by AMs. (e) Exosomes from the circulatory system (blue circle) of the AP model activate AMs cells by converting the phenotype from M2 to M1, which in turn aggravate the degree of lung injury. (f) Plasma-derived exosomes (purple circle) activate NLRP3 inflammasomes to induce pyrolysis of alveolar macrophages, thereby causing AP-related lung injury. AP, acute pancreatitis; PAAF, pancreatitis-associated ascitic fluid; AM, alveolar macrophage; NLRP3, NOD-like receptor protein 3.