title: Chronic Phenotype Characterization of a Large-Animal Model of Hereditary Tyrosinemia Type 1.
abstract: 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.
authors.affiliation: William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.
authors.forename: Faysal
authors.initials: F
authors.lastname: Elgilani
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Shennen A
authors.initials: SA
authors.lastname: Mao
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Glorioso
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Meng
authors.initials: M
authors.lastname: Yin
authors.affiliation: Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ianko D
authors.initials: ID
authors.lastname: Iankov
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Anisha
authors.initials: A
authors.lastname: Singh
authors.affiliation: Brami Biomedical, Inc., Minneapolis, Minnesota.
authors.forename: Bruce
authors.initials: B
authors.lastname: Amiot
authors.affiliation: Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Piero
authors.initials: P
authors.lastname: Rinaldo
authors.affiliation: Department of Comparative Medicine, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Marler
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Ehman
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, Oregon.
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota; Midwest Fetal Care Center, Children's Hospital and Clinics of Minnesota, Minneapolis, Minnesota.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Lillegard
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota; Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Hickey
authors.affiliation: William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota; Department of Surgery, Mayo Clinic, Rochester, Minnesota. Electronic address: nyberg.scott@mayo.edu.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Nyberg
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D054459:Elasticity Imaging Techniques; D005260:Female; D006537:Heptanoates / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000172:deficiency / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D053858:Metabolic Networks and Pathways; D010641:Phenotype; D017082:Portal Pressure; D034421:Sus scrofa; D014443:Tyrosine / Q000378:metabolism; D020176:Tyrosinemias / Q000473:pathology*; D015430:Weight Gain
chemical_list: D006537:Heptanoates; D014443:Tyrosine; C020804:succinylacetone; D006867:Hydrolases; C020156:fumarylacetoacetase