Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1

Abstract

Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in tyrosine catabolism. TT1 is clinically characterized by acute liver failure, development of hepatocellular carcinoma, renal and neurological problems, and consequently an extremely poor outcome. This review showed that the introduction of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) in 1992 has revolutionized the outcome of TT1 patients, especially when started pre-clinically. If started early, NTBC can prevent liver failure, renal problems, and neurological attacks and decrease the risk for hepatocellular carcinoma. NTBC has been shown to be safe and well tolerated, although the long-term effectiveness of treatment with NTBC needs to be awaited. The high tyrosine concentrations caused by treatment with NTBC could result in ophthalmological and skin problems and requires lifelong dietary restriction of tyrosine and its precursor phenylalanine, which could be strenuous to adhere to. In addition, neurocognitive problems have been reported since the introduction of NTBC, with hypothesized but as yet unproven pathophysiological mechanisms. Further research should be done to investigate the possible relationship between important clinical outcomes and blood concentrations of biochemical parameters such as phenylalanine, tyrosine, succinylacetone, and NTBC, and to develop clear guidelines for treatment and follow-up with reliable measurements. This all in order to ultimately improve the combined NTBC and dietary treatment and limit possible complications such as hepatocellular carcinoma development, neurocognitive problems, and impaired quality of life. Key Points Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) has been found to be generally safe and has clearly improved treatment and outcomes for patients with tyrosinemia type 1.

The future of gene-targeted therapy for hereditary tyrosinemia type 1 as a lead indication among the inborn errors of metabolism

“…Like HT3 patients, HT1 patients on NTBC can suffer from progressive and significant cognitive and ocular impairment [ 14 , 15 ], and an increasing body of literature is showing that HT1 patients on stable NTBC regimens can still develop HCC and require liver transplantation later in life [ 16 ]. Further, the cost of NTBC is high, equaling approximately 300 USD US for one 10 mg capsule [ 17 ], resulting in a cost of 1200 USD/day for effective treatment of a 20 kg child dosed at a typical 2 mg/kg [ 18 ] ( Figure 2 ). In 2019, a generic and bioequivalent version of NTBC called NITYR was introduced to the market.…”

In vivolentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions

“…Remarkably, animals treated adequately with NTBC showed increases in these liver injury and tumor-associated genes, which may explain the robust data now available in humans demonstrating development of cirrhosis and HCC in HT1 patients despite optimal and compliant NTBC therapy. [7][8][9][10]71,72 In addition, like wild-type animals, pigs treated with LV-FAH have normal undetectable levels of AFP at one year, which is in stark contrast to undertreated NTBC FAH-deficient animals. This further supports our proposal of LV-FAH as a cure for HT1 in lieu of chronic NTBC maintenance therapy, which does not prevent development of inflammation, fibrosis, and HCC due to residual progression of tyrosine metabolism through the degradation pathway resulting in production of toxic metabolites.…”

“…6 A number of case reports and series point to the development of fibrosis, cirrhosis, and HCC despite NTBC therapy, especially with later initiations of therapy. [7][8][9][10] The frequency of HCC within the limited follow-up period available for patients treated with NTBC appears to be <1% if started prior to 1 year of age, 7% if started between 1 and 2 years of age, 21% if started between 2 and 7 years of age, and 35% if started after 7 years of age. 11 Therefore, these patients require lifelong HCC surveillance with alphafetoprotein (AFP) levels drawn every 3 to 6 months.…”

Diazoxide-responsive hyperinsulinaemic hypoglycaemia in tyrosinaemia type 1

“…It is well known that adverse neurodevelopment is reported in 26–48% of patients with recurrent hyperinsulinaemic hypoglycaemia ( 10 ). Children with TT1 have an increased risk for neurocognitive problems, including a lower IQ and abnormal motor skills ( 11 ), which should not be aggravated by a delayed diagnosis or inadequate treatment of HH, especially because treatment with diazoxide is effective in children with TT1 and HH.…”