Liu, Yang

Abstract Background: Hemorrhagic necrotizing pancreatitis (HNP) is a highly lethal form of pancreatitis that lacks mechanism-based therapy. Intra-acinar enzyme activation is fundamental to pancreatitis initiation, yet it does not explain why only a subset of episodes progress to catastrophic hemorrhagic necrosis. Objective: To identify determinants of progression to lethal HNP and test a mechanism-based preventive intervention. Design: Using humanized trypsinogen mouse models and secretagogue regimens, we compared high-dose cerulein with low/moderate-dose cerulein and bombesin. We quantified pancreatic protease activity, performed blinded histopathologic scoring, assessed hemorrhage/vascular disruption, and evaluated enzyme localization and ductal injury by PRSS1 immunostaining. De-identified human pancreatic histology from HNP were examined. We tested a repurposed strategy using clinically approved agents for other indications: secretin to stimulate ductal fluid secretion and isosorbide mononitrate (ISMN) to promote ductal outflow via sphincter of Oddi relaxation. Results: High-dose cerulein induced robust intrapancreatic protease activation but predominantly caused edematous pancreatitis. Paradoxically, bombesin and low/moderate-dose cerulein elicited lower total pancreatic protease activity yet produced severe, frequently lethal HNP with vascular disruption and lobular ischemic necrosis. HNP was associated with intraductal enzyme accumulation and ductal injury. Secretin or ISMN alone showed limited protection, whereas combined secretin+ISMN prevented hemorrhagic necrotizing injury. Conclusion: Pancreatitis severity is determined not only by the magnitude of enzyme activation but also by where enzyme activity is exerted, implicating intraductal enzyme accumulation as a mechanistic determinant and therapeutic target in HNP. Coordinated enhancement of ductal secretion and outflow with clinically approved agents prevents HNP in vivo, supporting a translatable prevention strategy.

ABSTRACT Achalasia in a patient with liver cirrhosis decompensated by esophageal varices is an extremely rare presentation with complex management implications. We describe a case of achalasia and malnutrition in a male patient with esophageal varices treated by endoscopic ultrasound–guided botulinum toxin injection. After treatment, the patient's dysphagia dramatically improved, and his weight loss stabilized, which allowed an important window to remove the barrier of nutritional status for transplant candidacy. Endoscopic ultrasound–guided botulinum toxin injection to avoid varices is potentially a safer method for delivering botulinum toxin injection to the lower esophageal sphincter in a patient with esophageal varices.