Nitisinone for the treatment of hereditary tyrosinemia type I

Abstract

Introduction: Nitisinone has transformed the management of hereditary tyrosinemia type 1 (HT1) and if combined with neonatal screening could abolish most of the clinical manifestations of the disease. Hereditary tyrosinemia type 1 is a rare genetic disease due to fumarylacetoacetase (FAH) deficiency, which usually presents with liver failure. There is a high lifetime risk of developing hepatocellular carcinoma (HCC). The clinical manifestations stem from the cytotoxicity of tyrosine metabolites accumulating proximal to the metabolic defect. Nitisinone acts upstream of the defect to prevent the production of these metabolites. Nitisinone in combination with a tyrosine- and phenylalanine-restricted diet is the standard of care for patients with HT1, with transplantation reserved for where this fails. Where nitisinone is used preemptively, liver disease and HCC appear to be prevented, emphasizing the importance of effective neonatal screening. Treatment should be monitored by ensuring normal growth, close dietary control to maintain amino acid levels in the target range and ensuring nitisinone levels are within the therapeutic range. Nitisinone is well tolerated and has few adverse effects other than a predictable rise in plasma tyrosine levels. It is not currently indicated for routine use post liver transplantation. There are three current unmet concerns in the management of HT1: the lack of universal neonatal screening, the lack of a suitable liquid preparation and neurodevelopmental concerns.

Areas covered: This review used a Pubmed search for tyrosinemia and nitisinone as key words and sources available via the EMA website.

Expert opinion: The major future challenge is to combine nitisinone use with preemptive diagnosis by universal neonatal screening. The other major challenge in the management of HT1 is the need to understand the cause of the reported neurodevelopmental difficulties. New applications for nitisinone include alkaptonuria.

Keywords::

• guidelines
• inherited metabolic disease
• liver disease
• liver transplantation
• neonatal screening
• nitisinone
• tyrosinemia