title: Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers.
abstract: BACKGROUND
  Extrahepatic cholestasis sensitizes the liver to ischemia/reperfusion (I/R) injury during surgery for perihilar cholangiocarcinoma. It is associated with pre-existent sterile inflammation, microvascular perfusion defects, and impaired energy status. Statins have been shown to protect against I/R injury in normal and steatotic mouse livers. Therefore, the hepatoprotective properties of atorvastatin were evaluated in a rat model of cholestatic I/R injury.
  
  
  METHODS
  Male Wistar rats were subjected to 70% hepatic ischemia (during 30 min) at 7 days after bile duct ligation. Rats were randomized to atorvastatin treatment or vehicle-control in three test arms: (1) oral treatment with 5 mg/kg during 7 days after bile duct ligation; (2) intravenous treatment with 2.5, 5, or 7.5 mg/kg at 24 h before ischemia; and (3) intravenous treatment with 5 mg/kg at 30 min before ischemia. Hepatocellular damage was assessed by plasma alanine aminotransferase (ALT) and histological necrosis.
  
  
  RESULTS
  I/R induced severe hepatocellular injury in the cholestatic rat livers (~10-fold increase in ALT at 6 h after I/R and ~30% necrotic areas at 24 h after I/R). Both oral and intravenous atorvastatin treatment decreased ALT levels before ischemia. Intravenous atorvastatin treatment at 5 mg/kg at 24 h before ischemia was the only regimen that reduced ALT levels at 6 h after reperfusion, but not at 24 h after reperfusion. None of the tested regimens were able to reduce histological necrosis at 24 h after reperfusion.
  
  
  CONCLUSIONS
  Pre-treatment with atorvastatin did not protect cholestatic livers from hepatocellular damage after I/R. Clinical studies investigating the role of statins in the protection against hepatic I/R injury should not include cholestatic patients with perihilar cholangiocarcinoma. These patients require (pharmacological) interventions that specifically target the cholestasis-associated hepatopathology.
authors.affiliation: Department of Surgery, Surgical Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. jim.wiggers@gmail.com.
authors.forename: Jimme K
authors.initials: JK
authors.lastname: Wiggers
authors.affiliation: Department of Surgery, Surgical Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rowan F
authors.initials: RF
authors.lastname: van Golen
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joanne
authors.initials: J
authors.lastname: Verheij
authors.affiliation: Department of Surgery, Surgical Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Annemiek M
authors.initials: AM
authors.lastname: Dekker
authors.affiliation: Department of Surgery, Surgical Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: van Gulik
authors.affiliation: Department of Surgery, Surgical Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.heger@amc.nl.
authors.forename: Michal
authors.initials: M
authors.lastname: Heger
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000069059:Atorvastatin / Q000627:therapeutic use*; D001652:Bile Ducts / Q000601:surgery; D001651:Cholestasis, Extrahepatic / Q000150:complications*; D004334:Drug Administration Schedule; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008026:Ligation; D008099:Liver / Q000473:pathology*; D008297:Male; D009336:Necrosis / Q000209:etiology / Q000517:prevention & control; D011183:Postoperative Complications / Q000209:etiology / Q000517:prevention & control*; D020011:Protective Agents / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020011:Protective Agents; D000069059:Atorvastatin