Increased intracranial pressure in a porcine model of fulminant hepatic failure using amatoxin and endotoxin.
OBJECTIVE
The purpose of this study was to develop a clinically relevant porcine model of fulminant hepatic failure (FHF) by means of administration of amatoxin and endotoxin.


METHODS
Pigs were intraportally administered only saline in group 1 (n = 3), 1 microg/kg of lipopolysaccharide (LPS) in group 2 (n = 4), 0.1 mg/kg of alpha-amanitin in group 3 (n = 5), and amanitin plus LPS in group 4 (n = 9).


RESULTS
All the pigs in groups 1 and 2 survived with minimal changes in liver function tests. In contrast to the 60% mortality in group 3, all the pigs in group 4 died within 96 h, with a significant increase in aspartate transaminase at 24 h (9,757 +/- 2,167 IU/I). In addition, they demonstrated severe metabolic disorders, such as serum lactate accumulation, hypoglycemia, coagulopathy, plasma amino acid imbalance, and hyperammonemia. The intracranial pressure significantly increased to 17.8 +/- 2.5 mmHg immediately before death. Reversal of FHF in these pigs following orthotopic liver transplantation confirmed that the toxicity is liver-specific and that the graft liver is unaffected.


CONCLUSIONS
This porcine model of FHF induced by a combination of amanitin and LPS will be of much use in the development of new therapies for human FHF.
Takada
Y
Y
Department of Surgery, Institute of Clinical Medicine, Tsukuba University, Tsukuba City, Ibaraki, Japan. tyasutsu@md.tsukuba.ac.jp
Ishiguro
S
S
Fukunaga
K
K
Gu
M
M
Taniguchi
H
H
Seino
K I
KI
Yuzawa
K
K
Otsuka
M
M
Todoroki
T
T
Fukao
K
K
D000546:Amanitins / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D019586:Intracranial Hypertension / Q000209:etiology* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D008099:Liver / Q000473:pathology; D017093:Liver Failure / Q000139:chemically induced / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D016031:Liver Transplantation; D008297:Male; D013552:Swine
D000546:Amanitins; D008070:Lipopolysaccharides; C018207:amatoxin