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Long-Term Outcomes and Practical Considerations in The University of Groningen Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1 van Ginkel, Willem G; Rodenburg, Iris L; Harding, Cary O; Hollak, Carla E M; Heiner- Fokkema, M Rebecca; van Spronsen, Francjan J Published in: Paediatric drugs DOI: 10.1007/s40272-019-00364-4 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): van Ginkel, W. G., Rodenburg, I. L., Harding, C. O., Hollak, C. E. M., Heiner-Fokkema, M. R., & van Spronsen, F. J. (2019). Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1. Paediatric drugs, 21(6), 413-426. https://doi.org/10.1007/s40272-019- 00364-4 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Pediatric Drugs https://doi.org/10.1007/s40272-019-00364-4 LEADING ARTICLE Long‑Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1 Willem G. van Ginkel1 · Iris L. Rodenburg2 · Cary O. Harding3 · Carla E. M. Hollak4 · M. Rebecca Heiner‑Fokkema5 · Francjan J. van Spronsen1 © The Author(s) 2019 Abstract Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in tyrosine catabolism. TT1 is clinically character- ized 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-trifuoromethylbenzoyl)-1,3-cyclohexane- dione (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 efectiveness 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 life-long 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 hepa- tocellular carcinoma development, neurocognitive problems, and impaired quality of life. Key Points Treatment with 2-(2-nitro-4-trifuoromethylbenzoyl)- 1,3-cyclohexanedione (NTBC) has been found to be generally safe and has clearly improved treatment and * Francjan J. van Spronsen outcomes for patients with tyrosinemia type 1. [email protected] The long-term risks for complications associated with 1 Department of Metabolic Diseases, Beatrix Children’s tyrosinemia type 1 or treatment with NTBC are not yet Hospital, University Medical Center Groningen, University fully known and therefore strict follow-up is necessary. of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands Future challenges include the development of uniform 2 Department of Dietetics, University Medical Center guidelines for treatment and follow-up, and weighing the Groningen, University of Groningen, Groningen, risks, challenges, and costs of existing and alternative The Netherlands strategies for the treatment of tyrosinemia type 1. 3 Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, USA 4 Deparment of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands 5 Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Vol.:(0123456789) W. G. van Ginkel et al. 1 Introduction 2 NTBC and its Pharmacodynamics and Pharmacokinetics Tyrosinemia type 1 (TT1; OMIM276700), also called hepatorenal tyrosinemia, is an inborn error of metabolism, Naturally occurring triketones are produced by a num- caused by an autosomal recessive inherited defciency of the ber of plants and lichens. They are synthesized to prevent enzyme fumarylacetoacetate hydrolase (FAH), which is the growth of surrounding plants [15, 16]. NTBC is such a last enzyme in the tyrosine catabolic pathway converting triketone and was one of the frst to be used as a herbicide fumarylacetoacetate (FAA) into fumarate and acetoacetate. [17]. Experiments revealed that NTBC is a strong inhibitor One of the frst patients described with TT1 presented with of the enzyme 4HPPD [18–20], the second enzyme in the liver cirrhosis, renal tubular defects, and vitamin D-resistant catabolic cascade of tyrosine. 4HPPD catalyzes the conver- rickets, although the exact diagnosis was not clear at that sion of 4-hydroxyphenylpyruvate to homogentisate (Fig. 1). time [1]. Initially, the primary enzyme defect was consid- Through NTBC-mediated inhibition of the production of ered to be a defect of 4-hydroxyphenylpyruvate dioxygenase homogentisate, the synthesis of tocopherols and plastoqui- (4HPPD) [2, 3]. Some years later, it became apparent that nones in plants is blocked, thereby reducing the production the primary enzyme defciency was located more down- of chlorophyll. In this way, NTBC causes plants to bleach stream in the catabolic pathway of tyrosine at FAH (Fig. 1) [18]. In humans, it was postulated that NTBC could block [4]. further catabolism of tyrosine into its degradation products The only existing treatment at that time was dietary [11]. restriction of tyrosine and its precursor phenylalanine. The enzyme 4HPPD is a dioxygenase as its reaction Unfortunately, when only treated with a phenylalanine/ utilizes diatomic oxygen for oxidative decarboxylation as tyrosine-restricted diet, the outcome was extremely poor. well as aromatic ring hydroxylation [21]. NTBC rapidly and Many TT1 patients did not survive the initial period when tightly binds to the Fe(II)-containing active site of 4HPPD presenting with severe liver failure and its associated prob- after a multi-step process. Both NTBC and the substrate lems, including ascites and bleeding [5]. If patients survived 4-hydroxyphenylpyruvate have similar binding interac- this period, many died years later due to the development tions, with NTBC especially showing close afnity to the of hepatocellular carcinoma (HCC) or respiratory failure enzyme caused by interactions such as π-stacking. The caused by porphyria-like syndrome [5–7]. As a consequence, binding causes a rapid inactivation of the enzyme by creat- orthotopic liver transplantation (OLT) was long considered ing an almost irreversible 4HPPD inhibitor complex [20, the only defnitive option to treat the metabolic as well as 22–24]. In vitro experiments with tissue of wild-type rats the oncological problem [8–10]. revealed that a concentration of only 100 nM of NTBC was This all changed after the introduction of 2-(2-nitro- sufcient to block > 90% of the enzyme activity, with only a 4-trifuoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, small amount of activity returning after 7 h [19]. This strong also known as nitisinone) as a new treatment option in 1992 inhibitory reaction was also seen in healthy adult human [11]. NTBC proved to be a potent inhibitor of the enzyme participants, with a plasma half-life of 54 h after a single 4HPPD, which was frst thought to be responsible for the dose of NTBC [25]. disease. In this way, NTBC can prevent the production of In rats, NTBC showed a general tissue distribution pattern the toxic metabolites FAA, maleylacetoacetate, succinylace- shortly after dosing, with NTBC detectable in many diferent toacetate, and succinylacetone (SA), and thereby substan- tissues including plasma, eye (cornea and glands), liver, kid- tially improves the clinical outcome [12, 13]. However, as neys, lung, and a small amount in the brain [26]. However, a consequence of 4HPPD inhibition by NTBC treatment, retention of NTBC was especially apparent in the liver and tyrosine concentrations increase substantially further, mak- kidneys of
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