Abstract
In this chapter we describe the current Quebec NTBC Study protocol. Quebec’s unique characteristics have influenced the development of the protocol, including a high prevalence of hepatorenal tyrosinemia (HT1), universal newborn screening for HT1, availability of treatment with nitisinone (NTBC) and special diet, a large territory, where HT1 treatment is coordinated by a small number of centers. Screened newborns are seen within 3 weeks of birth. Patients with liver dysfunction (prolonged prothrombin time and/or international normalized ratio (INR) provide sensitive, rapidly available indicators) are treated by NTBC and special diet. The specific diagnosis is confirmed by diagnostic testing for succinylacetone (SA) in plasma and urine samples obtained before treatment. After an initial period of frequent surveillance, stable patients are followed every 3 months by assay of plasma amino acids and NTBC and plasma and urine SA. Abdominal ultrasound is done every 6 months. Patients have an annual visit to the coordinating center that includes multidisciplinary evaluations in metabolic genetics, hepatology, imaging (for abdominal ultrasound and magnetic resonance imaging) and other specialties as necessary. If hepatocellular carcinoma is suspected by imaging and/or because of progressive elevation of alphafetoprotein, liver transplantation is discussed. To date, no patient in whom treatment was started before 1 month of age has developed hepatocellular carcinoma, after surveillance for up to 20 years in some. This patient group is the largest in the world that has been treated rapidly following newborn screening. The protocol continues to evolve to adapt to the challenges of long term surveillance.
Submitted by Grant Mitchell for the Québec NTBC Study Group* including a section on diet therapy by Manon Bouchard.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- DRI:
-
Dietary reference intake
- HT1:
-
Hereditary tyrosinemia type 1
- INR:
-
International normalized ratio
- NTBC:
-
Nitisinone
- SA:
-
Succinylacetone
References
Grompe M, St-Louis M, Demers SI, Al-Dhalimy M, Leclerc B, Tanguay RM (1994) A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I. N Engl J Med 331(6):353–357. doi:10.1056/NEJM199408113310603
Hall MG, Wilks MF, Provan WM, Eksborg S, Lumholtz B (2001) Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers. Br J Clin Pharmacol 52(2):169–177
Larochelle J, Alvarez F, Bussieres JF, Chevalier I, Dallaire L, Dubois J, Faucher F, Fenyves D, Goodyer P, Grenier A, Holme E, Laframboise R, Lambert M, Lindstedt S, Maranda B, Melancon S, Merouani A, Mitchell J, Parizeault G, Pelletier L, Phan V, Rinaldo P, Scott CR, Scriver C, Mitchell GA (2012) Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Quebec. Mol Genet Metab 107(1–2):49–54. doi:10.1016/j.ymgme.2012.05.022
Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B (1992) Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 340(8823):813–817
Mitchell G, Larochelle J, Lambert M, Michaud J, Grenier A, Ogier H, Gauthier M, Lacroix J, Vanasse M, Larbrisseau A et al (1990) Neurologic crises in hereditary tyrosinemia. N Engl J Med 322(7):432–437. doi:10.1056/NEJM199002153220704
Mitchell GA, Grompe M, Lambert M, Tanguay RM (2001) Hypertyrosinemia. In: The Online Metabolic & Molecular Bases of Inherited Disease (OMMBID), 8th edn. McGraw Hill, New York
Acknowledgements
We thank Martyne Gosselin and Yolande Lefèvre for organizing the NTBC study since its inception and André Imbeau for financial support. Yves Théoret, Department of Pharmacology, CHU Sainte-Justine, developed and supervises the clinical NTBC assay. Denis Cyr, Robert Giguère and Paula Waters of CHUS in Sherbrooke, developed sensitive clinical assays for succinylacetone. Shupei Wang coordinated the reception and distribution of clinical samples. Hao Yang contributed to the preparation of this manuscript. We thank the Groupe d’Aide aux Enfants Tyrosinémiques du Québec (GAETQ) for its collaboration and for its support of families and patients affected by HT1. Jean Larochelle’s pioneering work with tyrosinemia was essential for establishing NTBC treatment for patients with HT1 in Québec.
Author Contributions
All authors revised the manuscript and provided comments as necessary. Manon Bouchard wrote the section about diet therapy. Grant Mitchell accepts responsibility for the accuracy of the text.
Author information
Authors and Affiliations
Consortia
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
The Québec NTBC Study Group. et al. (2017). The Québec NTBC Study. In: Tanguay, R. (eds) Hereditary Tyrosinemia. Advances in Experimental Medicine and Biology, vol 959. Springer, Cham. https://doi.org/10.1007/978-3-319-55780-9_17
Download citation
DOI: https://doi.org/10.1007/978-3-319-55780-9_17
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-55779-3
Online ISBN: 978-3-319-55780-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)