Toxicopathology of Simvastatin Induced Hepatic Damage: A Model for NASH?
Andre L Renno, Philipi C De Souza, Valeria B De Souza, Cristielle P Freitas, Marina Pavanello, Gilberto C Franchi, Jr, Alexandre E Nowill, Natalia GM Schenka, Rafael M Rocha, Glauce A Pinto, Fernando A Soares, Jose Vassallo, Laura F Rezende, Andre A Schenka. UNICAMP, Campinas, SP, Brazil; Hospital do Cancer A. C. Camargo, Sao Paulo, Brazil; UNIFAE, Sao Joao Da Boa Vista, SP, Brazil
Background: Nonalcoholic Steatohepatitis (NASH) is a silent syndrome with increasing incidence among metabolic syndrome patients. NASH can progress to liver fibrosis/cirrhosis, and is an important cause of cryptogenic cirrhosis. Currently, treatment of NASH is based solely on control of underlying diseases, with no specific measures against the liver lesions. In toxicology studies on statins, we have observed histopathologic signs of NASH in animals using simvastatin. Aim: to describe the microscopic hepatic lesions associated with oral intake of simvastatin and characterize a new experimental model of NASH.
Design: Sprague-Dawley rats (∼200g) were treated with simvastatin orally for 7 consecutive days at doses 20, 40, 60, 80 and 100 mg/kg/day (n=6/group). Simultaneously, a control group was composed by animals receiving only drug vehicle. After euthanasia, the livers were removed, histologically processed and analyzed for the presence of the main morphological features that allow for the diagnosis and staging of NASH according to established pathologic criteria. We also determined the plasma levels of liver enzymes (ALT and AST) by a colorimetric method. The experimental protocols were approved by the local instructional Committee for Ethics in Animal Experimentation.
Results: In the present protocol, 90% of animals treated with simvastatin developed laboratory features compatible with NASH, and/or at least borderline histological features of this disease. Animals treated with 100 mg/kg/day significantly increased serum levels of ALT (112.89±29.24 vs 58.78±2,08 U/mL of the control group) and AST (108,81±52,39 vs 53,99±25,82 U/mL of the control group) (p<0,05 ANOVA followed by Bonferroni's test). Moreover, none of the control animals developed any feature of NASH during the observation period. The most common grade of NASH (90%) was 2B, which is characterized by steatosis, ballooning degeneration and acinar inflammation. There were no cases of centrilobular fibrosis (characteristic of 2A NASH), as expected, since the protocol was not structured to achieve all of the characteristics of chronicity.
Conclusions: These results indicate that the oral administration of simvastatin (specially in doses greater than 80mg/kg/7 days) is a promising model of induction of NASH, which may be useful in future studies for the development of new pharmacological strategies for the specific treatment of NASH in humans.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 275, Wednesday Morning