The Role of Phosphate in Alcohol-Induced Experimental Pancreatitis

Abstract

See Covering the Cover synopsis on page 741.BACKGROUND & AIMS: Heavy alcohol consumption is a common cause of acute pancreatitis; however, alcohol abuse does not always result in clinical pancreatitis. As a consequence, the factors responsible for alcohol-induced pancreatitis are not well understood. In experimental animals, it has been difficult to produce pancreatitis with alcohol. Clinically, alcohol use predisposes to hypophosphatemia, and hypophosphatemia has been observed in some patients with acute pancreatitis. Because of abundant protein synthesis, the pancreas has high metabolic demands, and reduced mitochondrial function leads to organelle dysfunction and pancreatitis. We proposed, therefore, that phosphate deficiency might limit adenosine triphosphate synthesis and thereby contribute to alcoholinduced pancreatitis. METHODS: Mice were fed a lowphosphate diet (LPD) before orogastric administration of ethanol. Direct effects of phosphate and ethanol were evaluated in vitro in isolated mouse pancreatic acini. RESULTS: LPD reduced serum phosphate levels. Intragastric administration of ethanol to animals maintained on an LPD caused severe pancreatitis that was ameliorated by phosphate repletion. In pancreatic acinar cells, low-phosphate conditions increased susceptibility to ethanol-induced cellular dysfunction through decreased bioenergetic stores, specifically affecting total cellular adenosine triphosphate and mitochondrial function. Phosphate supplementation prevented ethanol-associated cellular injury. CONCLUSIONS: Phosphate status plays a critical role in predisposition to and protection from alcoholinduced acinar cell dysfunction and the development of acute alcohol-induced pancreatitis. This finding may explain why pancreatitis develops in only some individuals with heavy alcohol use and suggests a potential novel therapeutic approach to pancreatitis. Finally, an LPD plus ethanol provides a new model for studying alcohol-associated pancreatic injury.

New insights into the etiology, risk factors, and pathogenesis of pancreatitis in dogs: Potential impacts on clinical practice

“…While a certain daily consumption of alcohol is a significant risk factor for developing acute pancreatitis, certainly only the minority of human patients with such alcohol consumption develop pancreatitis 56 . Phosphate status (eg, hypophosphatemia) is a risk modifying factor in alcohol induced pancreatitis in people 57 . Unfortunately, these risk modifying factors are poorly understood in dogs fed a high fat diet.…”

Blood alcohol levels after standardized intake of alcohol are related to measured blood phosphate levels

“…There were only males included in this study and gastric ADH has been shown to be a factor mostly in males [3,13]. We have found no other human studies in this area, but a recent study in a mouse model found no difference in peak BAC related to blood phosphate level [14].…”

Murine Chronic Pancreatitis Model Induced by Partial Ligation of the Pancreatic Duct Encapsulates the Profile of Macrophage in Human Chronic Pancreatitis

“…More importantly, the cerulein-induced AP model is mostly mild edematous pancreatitis with only a small amount of necrosis (38,39), which is not suitable for simulating clinical severe acute pancreatitis (SAP). AP models constructed by specific diet or surgery in mice can often better simulate the etiology of human AP and has higher clinical transformation value, such as alcoholic AP model constructed by oral administration of ethanol and palmitoleic acid (40), alcoholic AP with a background of hypophosphatemia constructed by lowphosphate diet (LPD) feeding followed by orogastric administration of ethanol (41), hypertriglyceridemic AP In AP (3d) and the early phase of CP (7d), macrophages were predominantly M1 subtype (F4/80+iNOS+ cells). From 14d onwards, it was the M2 subtype (F4/80+CD206+ cells) of macrophages that was predominant, which was peaked at 21d.…”