In 1992, Sven Lindstedt and colleagues 1 Lindstedt S Holme E Lock EA Hjalmarson O Strandvik B Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. reported the first study using 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (nitisinone) to treat five children with hereditary tyrosinaemia type 1. This disorder of tyrosine degradation has a high morbidity and mortality in the early years of life, primarily due to life-threatening hepatic disease including liver failure and hepatocellular carcinoma. 1 Lindstedt S Holme E Lock EA Hjalmarson O Strandvik B Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. An Editorial in The Lancet at the time called this a “radical new approach to the treatment of a serious, life-threatening condition”. 2 The Lancet
New treatment for tyrosinaemia. It was indeed radical, considering that nitisinone was initially developed for the agricultural industry as an herbicide. Although the mechanism of action of nitisinone was not initially understood, toxicology studies revealed that it was a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme in the tyrosine degradation pathway upstream of the enzyme deficiency of hereditary tyrosinaemia type 1. 3 From weed killer to wonder drug. Sven Lindstedt and his colleague, Elisabeth Holme, at Gothenburg University (Gothenburg, Sweden) were consulted because of their expertise with regard to this enzyme and their experience with patients with hereditary tyrosinaemia type 1. At the time, management of children with this condition was limited to dietary restriction of phenylalanine and tyrosine, which was remarkably ineffective, followed by liver transplantation. Treatment with nitisinone in five individuals with hereditary tyrosinaemia type 1 showed dramatic response and these findings, together with additional clinical trials, led to the authorisation of nitisinone by the US Food and Drug Administration in 2002 and the European Medicines Agency in 2005. Nitisinone effectively revolutionised the care of children with hereditary tyrosinaemia type 1, substantially improving quality of life and life expectancy. 4 Nontransplant treatment of tyrosinemia. However, nitisinone's inhibition of tyrosine catabolism leads to increased plasma tyrosine levels, necessitating dietary management to maintain tyrosine levels at less than 500 μmol/L. Known side-effects of nitisinone include cytopenias and corneal keratopathy due to high concentrations of tyrosine. 4 Nontransplant treatment of tyrosinemia. However, although nitisinone has become the standard of care for hereditary tyrosinaemia type 1, long-term follow-up data on safety are still needed to determine the potential consequences of prolonged nitisinone use.