A novel stable reproducible model of hepatic failure in canines.
BACKGROUND
Stable and reproducible large animal models of hepatic failure, which allow the assessment of liver-assist devices, are not available. Our objective was to develop a physiologically stable animal model of hepatic failure on which the safety and efficacy of an extracorporeal liver-assist device can be tested. We hypothesized that a surgical model which consists of an end-to-side portocaval shunt combined with common bile duct ligation and transection would create hepatic failure with: (1) elevations in amino transferases, total bilirubin, and ammonia; (2) a decrease in the ratio of branched chain to aromatic amino acids; and (3) histologic evidence of hepatic injury.


METHODS
Eleven mongrel dogs underwent common bile duct transection and an end-to-side portocaval shunt. Aminotransferases (AST, ALT), total bilirubin, ammonia, and branched chain and aromatic amino acids were measured prior to operation (baseline) and after 9 days. A necropsy was performed on Postoperative Day 9 and liver biopsies were obtained for histology.


RESULTS
By Postoperative Day 9, AST, ALT, total bilirubin, and ammonia values were significantly elevated compared to baseline (P < 0.02). The ratio of branched chain to aromatic amino acids was significantly reduced compared to baseline (P < 0.003). There was histologic evidence of cholestasis and inflammation.


CONCLUSIONS
Portocaval shunt with common bile duct transection produces liver failure with elevations in aminotransferases, total bilirubin, and ammonia, a decreased branched chain to aromatic amino acid ratio, and histologic inflammation. Unlike ischemic or chemically induced models of liver failure, the dogs were hemodynamically and neurologically stable. This model can be used to test the safety and efficacy of liver-assist devices aimed at temporizing the detoxification functions of the failing liver.
Awad
S S
SS
Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA.
Hemmila
M R
MR
Soldes
O S
OS
Sawada
S
S
Rich
P B
PB
Mahler
S
S
Gargulinski
M
M
Hirschl
R B
RB
Bartlett
R H
RH
D000410:Alanine Transaminase / Q000097:blood; D000597:Amino Acids, Branched-Chain / Q000097:blood; D000598:Amino Acids, Cyclic / Q000097:blood; D000641:Ammonia / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D003135:Common Bile Duct / Q000502:physiology; D004195:Disease Models, Animal; D004285:Dogs; D006439:Hemodynamics; D008099:Liver / Q000473:pathology; D017093:Liver Failure / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D019164:Liver, Artificial; D009504:Neutrophils / Q000473:pathology; D011167:Portacaval Shunt, Surgical; D015203:Reproducibility of Results
D000597:Amino Acids, Branched-Chain; D000598:Amino Acids, Cyclic; D015415:Biomarkers; D000641:Ammonia; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin