title: Acute hypercalcemia causes acute pancreatitis and ectopic trypsinogen activation in the rat.
abstract: OBJECTIVE
  Clinical and experimental observations have associated acute and chronic hypercalcemia with pancreatitis. The aim of this study was to determine whether acute hypercalcemia can induce acute pancreatitis and, if so, whether the pathogenesis involves premature protease activation.
  
  
  METHODS
  Rats given bolus infusions of CaCl2 (200 mg/kg; n = 76) were compared with saline-treated controls (n = 40). Serum [Ca2+], serum amylase activity, trypsinogen activation peptide (TAP) concentration in serum and pancreatic tissue, pancreatic wet/dry weight ratio, and histology were assessed for 24 hours. For dose-response analysis, CaCl2 was injected at a dose of 50-200 mg/kg, and the aforementioned indices were assayed for 1 hour (n = 5 each).
  
  
  RESULTS
  There were no significant changes in the controls. Calcium infusion increased serum [Ca2+] 3-fold after 5 minutes (P < 0.001). Within 1 hour, serum amylase (2.5-fold) and tissue TAP (3-fold) levels increased along with macroscopic and microscopic edema formation and leukocytic infiltration. The extent of the changes at 1 hour correlated with the calcium dose. Amylase and tissue TAP concentrations remained elevated until 24 hours when serum TAP concentration had increased (P < 0.001) and focal acinar necrosis became evident.
  
  
  CONCLUSIONS
  Acute experimental hypercalcemia induces dose-dependent morphological alterations characteristic of acute pancreatitis, acute hyperamylasemia, and early ectopic trypsinogen activation. This supports the pathophysiological relevance of excess calcium and offers a possible pathogenetic mechanism for its association with clinical pancreatitis.
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mithöfer
authors.forename: C
authors.initials: C
authors.lastname: Fernández-del Castillo
authors.forename: T W
authors.initials: TW
authors.lastname: Frick
authors.forename: K B
authors.initials: KB
authors.lastname: Lewandrowski
authors.forename: D W
authors.initials: DW
authors.lastname: Rattner
authors.forename: A L
authors.initials: AL
authors.lastname: Warshaw
mesh_terms: D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D002118:Calcium / Q000097:blood; D002122:Calcium Chloride / Q000008:administration & dosage; D016009:Chi-Square Distribution; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006934:Hypercalcemia / Q000139:chemically induced / Q000150:complications*; D016014:Linear Models; D008297:Male; D009336:Necrosis; D009842:Oligopeptides / Q000097:blood / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010195:Pancreatitis / Q000209:etiology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014362:Trypsinogen / Q000378:metabolism*
chemical_list: D009842:Oligopeptides; C080396:trypsinogen activation peptide; D014362:Trypsinogen; D000681:Amylases; D002122:Calcium Chloride; D002118:Calcium