Chronic Phenotype Characterization of a Large-Animal Model of Hereditary Tyrosinemia Type 1

Faysal Elgilani, Shennen A. Mao, Jaime M. Glorioso, Meng Yin, Ianko D. Iankov, Anisha Singh, Bruce Amiot, Piero Rinaldo, Ronald J. Marler, Richard L. Ehman, Markus Grompe, Joseph B. Lillegard, Raymond D. Hickey, Scott L. Nyberg

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)33-41
Number of pages9
JournalAmerican Journal of Pathology
Issue number1
StatePublished - Jan 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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