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 Lorne Ehman, Markus Grompe, Joseph B. Lillegard, Raymond Hickey, Scott Nyberg

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7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)33-41
Number of pages9
JournalAmerican Journal of Pathology
Volume187
Issue number1
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Elgilani, F., Mao, S. A., Glorioso, J. M., Yin, M., Iankov, I. D., Singh, A., Amiot, B., Rinaldo, P., Marler, R. J., Ehman, R. L., Grompe, M., Lillegard, J. B., Hickey, R., & Nyberg, S. (2017). Chronic Phenotype Characterization of a Large-Animal Model of Hereditary Tyrosinemia Type 1. American Journal of Pathology, 187(1), 33-41. https://doi.org/10.1016/j.ajpath.2016.09.013