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

Research output: Contribution to journalArticle

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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

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Tyrosinemias
Swine
Animal Models
Phenotype
Fibrosis
Weight Gain
Liver Diseases
Deficiency Diseases
Protective Agents
Acute Liver Failure
Portal Hypertension
Liver Cirrhosis
Tyrosine
Hepatocellular Carcinoma
Chronic Disease
fumarylacetoacetase
Parturition
Enzymes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Chronic Phenotype Characterization of a Large-Animal Model of Hereditary Tyrosinemia Type 1. / Elgilani, Faysal; Mao, Shennen A.; Glorioso, Jaime M.; Yin, Meng; Iankov, Ianko D.; Singh, Anisha; Amiot, Bruce; Rinaldo, Piero; Marler, Ronald J; Ehman, Richard Lorne; Grompe, Markus; Lillegard, Joseph B.; Hickey, Raymond; Nyberg, Scott.

In: American Journal of Pathology, Vol. 187, No. 1, 01.01.2017, p. 33-41.

Research output: Contribution to journalArticle

Elgilani, F, Mao, SA, Glorioso, JM, Yin, M, Iankov, ID, Singh, A, Amiot, B, Rinaldo, P, Marler, RJ, Ehman, RL, Grompe, M, Lillegard, JB, Hickey, R & Nyberg, S 2017, 'Chronic Phenotype Characterization of a Large-Animal Model of Hereditary Tyrosinemia Type 1', American Journal of Pathology, vol. 187, no. 1, pp. 33-41. https://doi.org/10.1016/j.ajpath.2016.09.013
Elgilani, Faysal ; Mao, Shennen A. ; Glorioso, Jaime M. ; Yin, Meng ; Iankov, Ianko D. ; Singh, Anisha ; Amiot, Bruce ; Rinaldo, Piero ; Marler, Ronald J ; Ehman, Richard Lorne ; Grompe, Markus ; Lillegard, Joseph B. ; Hickey, Raymond ; Nyberg, Scott. / Chronic Phenotype Characterization of a Large-Animal Model of Hereditary Tyrosinemia Type 1. In: American Journal of Pathology. 2017 ; Vol. 187, No. 1. pp. 33-41.
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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.",
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AU - Amiot, Bruce

AU - Rinaldo, Piero

AU - Marler, Ronald J

AU - Ehman, Richard Lorne

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AU - Hickey, Raymond

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