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

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• 作者：Faysal Elgilani^&lowast ; ; Shennen A. Mao^&dagger ; ; Jaime M. Glorioso^&dagger ; ; Meng Yin^&Dagger ; ; Ianko D. Iankov^§ ; ; Anisha Singh^&dagger ; ; Bruce Amiot^¶ ; ; Piero Rinaldo^§ ; ; Ronald J. Marler^‖ ; Richard L. Ehman^&Dagger ; ; Markus Grompe^&lowast ; &lowast ; ; Joseph B. Lillegard^&dagger ; ; ^&dagger ; &dagger ; ; Raymond D. Hickey^&dagger ; ; ^&Dagger ; &Dagger ; ; Scott L. Nyberg^&lowast ; ; ^&dagger ; ; ^{nyberg.scott@mayo.edu}
• 刊名：The American Journal of Pathology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：187
• 期：1
• 页码：33-41
• 全文大小：1909 K
• 卷排序：187

文摘

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.