Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec

Larochelle, J; Álvarez, Fernando; Bussières, J.-F.; Chevalier, Isabelle; Dallaire, Louis; Dubois, Josée; Faucher, Frédéric; Fenyves, Daphna; Goodyer, Paul; Grenier, A; Holme, Elisabeth; Laframboise, Rachel; Lambert, Marie; Lindstedt, Sven; Maranda, Bruno; Mélancon, Serge B.; Mérouani, Aïcha; Mitchell, John; Parizeault, Guy; Pelletier, Luc G.; Phan, Véronique; Rinaldo, Piero; Scott, C. Ronald; Scriver, Charles R.; Mitchell, Grant A.

doi:10.1016/j.ymgme.2012.05.022

Cited by 127 publications

(189 citation statements)

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“…NTBC has led to remarkable improvement in the outcome of HT1 (Larochelle et al 2012;de Laet et al 2013). It inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase at a stage before the metabolic defect, but increases tyrosine concentrations as a consequence, necessitating a diet restriction of tyrosine and its indispensable precursor phenylalanine.…”

Section: Introductionmentioning

confidence: 99%

What Is the Best Blood Sampling Time for Metabolic Control of Phenylalanine and Tyrosine Concentrations in Tyrosinemia Type 1 Patients?

et al. 2017

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Background: Treatment of hereditary tyrosinemia type 1 with nitisinone and phenylalanine and tyrosine restricted diet has largely improved outcome, but the best blood sampling time for assessment of metabolic control is not known. Aim: To study diurnal and day-to-day variation of phenylalanine and tyrosine concentrations in tyrosinemia type 1 patients. Methods: Eighteen tyrosinemia type 1 patients aged >1 year (median age 7.9 years; range 1.6-20.7) were studied. Capillary blood samples were collected 4 times a day (T1: pre-breakfast, T2: pre-midday meal, T3: before evening meal, and T4: bedtime) for 3 days. Linear mixed-effect models were used to investigate diurnal and day-to-day variation of both phenylalanine and tyrosine. Results: The coefficients of variation of phenylalanine and tyrosine concentrations were the lowest on T1 (13.8% and 14.1%, respectively). Tyrosine concentrations did not significantly differ between the different time points, but phenylalanine concentrations were significantly lower at T2 and T3 compared to T1 (50.1 mmol/L, 29.8 mmol/L, and 37.3 mmol/L, respectively). Conclusion: Our results indicated that for prevention of too low phenylalanine and too high tyrosine concentrations, measurement of phenylalanine and tyrosine pre-midday meal would be best, since phenylalanine concentrations are the lowest on that time point. Our results also indicated that whilst blood tyrosine concentrations were stable over 24 h, phenylalanine fluctuated. Day-to-day variation was most stable after an overnight fast for both phenylalanine and tyrosine. Therefore, in tyrosinemia type 1 patients the most reliable time point for measuring phenylalanine and tyrosine concentrations to enable interpretation of metabolic control is pre-breakfast.

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Section: Introductionmentioning

confidence: 99%

What Is the Best Blood Sampling Time for Metabolic Control of Phenylalanine and Tyrosine Concentrations in Tyrosinemia Type 1 Patients?

et al. 2017

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“…Implementation in neonatal blood spot screening (NBS) and treatment with 2-(2-nitro-4-trifluoromethyl-benzyl)-1,3-cyclohexanedione (NTBC) to prevent accumulation of toxic metabolites by inhibiting tyrosine catabolism upstream from the primary enzymatic defect has largely improved clinical outcome (Larochelle et al 2012;Mayorandan et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

et al. 2014

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Tyrosinemia type 1 (HT1) is an inborn error of tyrosine catabolism caused by fumarylacetoacetase deficiency. Biochemically, this results in accumulation of toxic metabolites including succinylacetone. Clinically, HT1 is characterized by severe liver, kidney, and neurological problems. Treatment with NTBC and dietary restriction of tyrosine and phenylalanine have strongly improved outcome, but impaired neurocognitive development has been reported. Whether impaired neurocognitive outcome results from high blood tyrosine or low blood phenylalanine concentrations is currently unknown. In this report, two HT1 newborns, diagnosed by neonatal screening, are presented. The first patient showed low phenylalanine concentrations, growth retardation, neurological impairments, and skin problems, clearly improving after institution of phenylalanine supplementation (~30 mg/kg/ day) at age 6 months, while both blood phenylalanine and tyrosine concentrations increased. In the second patient, phenylalanine supplementation (~20 mg/kg/day) was initiated as soon as low phenylalanine concentrations were observed at age 19 days. On this regimen, blood phenylalanine concentrations increased, and hypophenylalaninemia was less frequently observed than in the first patient, whereas blood tyrosine concentrations tended to increase. Clinically, no growth, neurological, or skin problems have been observed. The combination of knowledge obtained from these cases suggests that hypophenylalaninemia rather than hypertyrosinemia during the first months of life may impair neurocognitive development in young HT1 infants. Phenylalanine supplementation should really be considered in HT1 patients with consistently low blood phenylalanine concentrations during the first months of life. However, the minimal phenylalanine concentrations acceptable and the optimal phenylalanine supplementation regimen require further investigation.

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“…However, if NTBC were started before 1 month, it could prevent liver disease. 8 By treating infants with NTBC, HT-1 evolves into a nonprogressive disease, with normal liver function; however, toxic metabolites continue to be produced, so the risk of HCC is not completely eliminated. 9 Increases in the levels of AFP, or slow decreases in their levels, or non-normalizing concentrations of AFP after NTBC treatment are important predictors of HCC development.…”

Section: Discussionmentioning

confidence: 99%

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Bahador

Dehghani²,

Geramizadeh³

et al. 2015

Exp Clin Transplant

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Objectives: This study sought to determine the prevalence of hepatocellular carcinoma and other premalignant lesions in children with hereditary tyrosinemia type 1 who had undergone an orthotopic liver transplant at the Shiraz Transplant Center, in Shiraz, Iran. Materials and Methods: Between September 2006, and June 2011, thirty-six patients with hereditary tyrosinemia type 1 received a liver transplant from a deceased (whole or split) or a living-related donor. Clinical records and pathologic specimens, before and after surgery, for each case were reviewed. In addition, ultrasound, abdominal computed tomographic imaging scan findings, and levels of alpha-fetoprotein were recorded. Results: Twenty-two patients with hepatic nodules larger than 10 mm underwent a Tru-Cut needle biopsy before their liver transplant. In 2 patients, a diagnosis of hepatocellular carcinoma was made by pathologic examination; in the other 20, cirrhosis was confirmed with no evidence of malignancy. After pathologic examination of the explanted livers, the largest nodules in the 36 patients were 35 mm. Five cases had at least 1 nodule of hepatocellular carcinoma. Three of the other patients had small cell dysplasia in some of nodules. All 5 cases with hepatocellular carcinoma were patients older than 2 years of age (19 patients were older than 2 years of age). All patients with hepatocellular carcinoma received pretransplant nitisinone treatment. All patients with hepatocellular carcinoma after their liver transplant are alive at the time of this writing. Conclusions: The prevalence of cell dysplasia and hepatocellular carcinoma in children with hereditary tyrosinemia type 1 in our study is not as high as that reported previously, so it appears that patients older than 2 years of age require a liver transplant.

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Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec

Cited by 127 publications

References 19 publications

What Is the Best Blood Sampling Time for Metabolic Control of Phenylalanine and Tyrosine Concentrations in Tyrosinemia Type 1 Patients?

What Is the Best Blood Sampling Time for Metabolic Control of Phenylalanine and Tyrosine Concentrations in Tyrosinemia Type 1 Patients?

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

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