Nitisinone in the treatment of hereditary tyrosinaemia type 1.

Hereditary tyrosinaemia type 1 (HT-1) is a rare genetic disease caused by mutations in the gene for the enzyme fumarylacetoacetase. It usually presents with liver failure but can be manifest as chronic liver disease. Rarely, it may present with nonhepatic manifestations such as renal dysfunction, porphyria-like illness or cardiomyopathy. There is a high lifetime risk of developing hepatocellular carcinoma (HCC). Prior to the development of liver transplantation, most patients died in childhood.The clinical manifestations stem from the cytotoxicity of tyrosine metabolites accumulating proximal to the metabolic defect. Nitisinone acts on tyrosine metabolism upstream of the defect to prevent the production of these metabolites. Nitisinone is used in combination with a tyrosine- and phenylalanine-restricted diet. Nitisinone has transformed the natural history of tyrosinaemia. Liver failure is controlled in 90% of patients, those with chronic liver disease improve and nonhepatic manifestations are abolished. Nitisinone is well tolerated and has few adverse effects other than a predictable rise in plasma tyrosine levels. Nitisinone provides protection against HCC if it is started in infancy, but if commenced after the age of 2 years, a significant risk of HCC remains. Furthermore, where nitisinone is used pre-emptively, liver disease appears to be prevented, suggesting the importance of neonatal screening for tyrosinaemia where possible. Nitisinone is indicated for all children with HT-1, and liver transplantation is only indicated where nitisinone fails, or where the development of HCC is likely or suspected.