TY - JOUR
T1 - Chronic Phenotype Characterization of a Large-Animal Model of Hereditary Tyrosinemia Type 1
AU - Elgilani, Faysal
AU - Mao, Shennen A.
AU - Glorioso, Jaime M.
AU - Yin, Meng
AU - Iankov, Ianko D.
AU - Singh, Anisha
AU - Amiot, Bruce
AU - Rinaldo, Piero
AU - Marler, Ronald J.
AU - Ehman, Richard L.
AU - Grompe, Markus
AU - Lillegard, Joseph B.
AU - Hickey, Raymond D.
AU - Nyberg, Scott L.
N1 - Publisher Copyright:
© 2017 American Society for Investigative Pathology
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease caused by deficiency in fumarylacetoacetate hydrolase, the last enzyme in the tyrosine catabolic pathway. In this study, we investigated whether fumarylacetoacetate hydrolase deficient (FAH−/−) pigs, a novel large-animal model of HT1, develop fibrosis and cirrhosis characteristic of the human disease. FAH−/− pigs were treated with the protective drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3 cyclohexandione (NTBC) at a dose of 1 mg/kg per day initially after birth. After 30 days, they were assigned to one of three groups based on dosing of NTBC. Group 1 received ≥0.2 mg/kg per day, group 2 cycled on/off NTBC (0.05 mg/kg per day × 1 week/0 mg/kg per day × 3 weeks), and group 3 received no NTBC thereafter. Pigs were monitored for features of liver disease. Animals in group 1 continued to have weight gain and biochemical analyses comparable to wild-type pigs. Animals in group 2 had significant cessation of weight gain, abnormal biochemical test results, and various grades of fibrosis and cirrhosis. No evidence of hepatocellular carcinoma was detected. Group 3 animals declined rapidly, with acute liver failure. In conclusion, the FAH−/− pig is a large-animal model of HT1 with clinical characteristics that resemble the human phenotype. Under conditions of low-dose NTBC, FAH−/− pigs developed liver fibrosis and portal hypertension, and thus may serve as a large-animal model of chronic liver disease.
AB - Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease caused by deficiency in fumarylacetoacetate hydrolase, the last enzyme in the tyrosine catabolic pathway. In this study, we investigated whether fumarylacetoacetate hydrolase deficient (FAH−/−) pigs, a novel large-animal model of HT1, develop fibrosis and cirrhosis characteristic of the human disease. FAH−/− pigs were treated with the protective drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3 cyclohexandione (NTBC) at a dose of 1 mg/kg per day initially after birth. After 30 days, they were assigned to one of three groups based on dosing of NTBC. Group 1 received ≥0.2 mg/kg per day, group 2 cycled on/off NTBC (0.05 mg/kg per day × 1 week/0 mg/kg per day × 3 weeks), and group 3 received no NTBC thereafter. Pigs were monitored for features of liver disease. Animals in group 1 continued to have weight gain and biochemical analyses comparable to wild-type pigs. Animals in group 2 had significant cessation of weight gain, abnormal biochemical test results, and various grades of fibrosis and cirrhosis. No evidence of hepatocellular carcinoma was detected. Group 3 animals declined rapidly, with acute liver failure. In conclusion, the FAH−/− pig is a large-animal model of HT1 with clinical characteristics that resemble the human phenotype. Under conditions of low-dose NTBC, FAH−/− pigs developed liver fibrosis and portal hypertension, and thus may serve as a large-animal model of chronic liver disease.
UR - http://www.scopus.com/inward/record.url?scp=85006355951&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85006355951&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2016.09.013
DO - 10.1016/j.ajpath.2016.09.013
M3 - Article
C2 - 27855279
AN - SCOPUS:85006355951
SN - 0002-9440
VL - 187
SP - 33
EP - 41
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -