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United States Department of Agriculture

Agricultural Research Service

Title: Long-Term Therapy with Ntbc and Tyrosine Restricted Diet in a Murine Model of Hereditary Tyrosinemia Type I.

Authors
item Al-Dhalimy, M. - DEPT MOLE & MED GEN, OR
item Overturf, Kenneth
item Finegold, M. - DEPT PATH TX CHILD HOSP
item Grompe, M. - DEPT PEDIATRICS OREGON

Submitted to: Molecular Genetics and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 1, 2001
Publication Date: January 1, 2002

Interpretive Summary: Hereditary tyrosinemia type 1 (HT1) is caused by deficiency of the enzyme necessary for tyrosine catabolism. In humans, disease symptoms include liver failure, liver cancer, and kidney problems. In the past, dietary tyrosine restriction and liver transplantation were the only effective forms of treatment. Recently, the drug NTBC has been used with great success. Early use can prevent and even reverse liver problems. NTBC therapy was discovered relatively recently and for this reason long-term follow-up data are limited. In particular, the risk for development of liver cancer is not known. Some patients have developed liver cancer while on NTBC treatment, but earlier treatment might prevent the development of the disease. We previously reported that the use of NTBC in a murine model of HT1 abolished acute liver failure but did not prevent the development of liver cancer in the setting of non-restricted protein intake. Here we present the results obtained with higher doses of NTBC plus dietary tyrosine restriction on long-term follow up. Liver tests were completely corrected with this regimen and cancer free survival was improved when compared to historical controls. However, while no HT1 animals had liver cancer at age 13 months, the incidence was 13 percent at age 18 months and 17 percent after 24 months. Thus, even the most stringent therapy could not prevent the emergence of liver cancer in the mouse model of HT1.

Technical Abstract: In human patients with hereditary tyrosinemia type I (HT1) a combination therapy of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexane dione (NTBC) and dietary restriction of phenylalanine and tyrosine is currently widely used. We previously reported that the use of NTBC in a murine model of HT1 abolished acute liver failure but did not prevent the development of hepatocellular carcinoma (HCC) in the setting of non-restricted protein intake. Here we present the results obtained with higher doses of NTBC plus dietary tyrosine restriction on long-term follow up (>2 years). Liver function tests and succinylacetone levels were completely corrected with this regimen and cancer free survival was improved when compared to historical controls. However, while no HT1 animals had HCC at age 13 months, the incidence was 2/16 (13%) at age 18 months and 1/6 (17%) after 24 months. Thus, even the most stringent therapy ycould not prevent the emergence of HCC in the mouse model of HT1, even whe initiated prematally.

Last Modified: 8/1/2014
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