Nitisinone is an inhibitor of the tyrosine catabolism that is used to treat hereditary tyrosinemia, type 1, in which accumulation of intermediates of tyrosine metabolism causes severe and progressive hepatic and renal injury. Nitisinone has been associated with mild, transient serum aminotransferase elevations, but has not been linked to instances of clinically apparent acute liver injury or jaundice.


Nitisinone (nye tis’ i none) is a small molecule inhibitor of 4-hydroxyphenylpyruvate the second enzymatic step in tyrosine metabolism (see Figure 1). Developed initially as an herbicide, it was later found to be beneficial in hereditary type 1 tyrosinemia in which the absence of fumarylacetoacetate hydrolase (FAH), the fifth step in tyrosine catabolism, causes buildup of toxic intermediates that cause early onset liver failure and severe renal tubular dysfunction. Treatment of infants and children with nitisinone combined with a low protein diet led to reversal of liver failure and correction of renal tubular dysfunction, allowing for normal growth and development. Children treated before the onset of liver failure avoided the need for liver transplantation and did not develop hepatocellular carcinoma, common outcomes before the availability of this agent. Nitisinone was approved as an orphan drug for use in tyrosinemia, type 1, in the United States in 2002. Nitisinone is available in tablets of 2, 5, 10 and 20 mg and as an oral suspension of 4 mg/mL under the brand name Orfadin. The recommended dose is 0.5 mg/kg orally given twice daily, but monitoring with drug and tyrosine levels is usually recommended and can lead to dose modification. Side effects are infrequent, but serious complications include corneal irritation, opacities and ulcers, skin rash, developmental delay and intellectual disability, leukopenia and thrombocytopenia. Most of these serious side effects of nitisinone are thought to be due to the elevation in plasma tyrosine levels which typically increase ten-fold during treatment. These increases can be partially prevented by limiting tyrosine and phenylalanine intake by a low or limited protein diet, a necessary component in the therapy of this disease.

Figure 1. Metabolic Disorders of Tyrosine and Nitisinone Action.

Nitisinone fig 1


Type 1 tyrosinemia is a rare disease and clinical experience with use of nitisinone is limited. Therapy can be accompanied by mild elevations in serum aminotransferase levels, but these are generally mild (less than 3 times the upper limit of normal [ULN]) and often resolve even without dose modification. The aminotransferase elevations are not accompanied by symptoms or increases in serum alkaline phosphatase or bilirubin levels and rarely require dose modification. There have been no reports of clinically apparent liver injury attributed to nitisinone in the treatment of tyrosinemia or in experimental studies of its use in other disorders of tyrosine metabolism such as alkaptonuria.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which nitisinone causes serum aminotransferase elevations is unclear. Increased intrahepatic levels of tyrosine or 4-hydroxyphenylacetate may have mild toxic effects on hepatocytes or other tissues leading to mild and transient aminotransferase release.

Drug Class: Genetic Disorder Agents (Liver Diseases), Enzyme Inhibitors



Nitisinone – Orfadin®


Genetic Disorder Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 05 October 2016

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