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

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Molecular Genetics and Metabolism (Impact Factor: 2.63). 07/2012; 107(1-2):49-54. DOI: 10.1016/j.ymgme.2012.05.022
Source: PubMed


Hepatorenal tyrosinemia (HT1, fumarylacetoacetate hydrolase deficiency, MIM 276700) can cause severe hepatic, renal and peripheral nerve damage. In Québec, HT1 is frequent and neonatal HT1 screening is practiced. Nitisinone (NTBC, Orfadin ®) inhibits tyrosine degradation prior to the formation of toxic metabolites like succinylacetone and has been offered to HT1 patients in Québec since 1994.
We recorded the clinical course of 78 Québec HT1 patients born between 1984 and 2004. There were three groups: those who never received nitisinone (28 patients), those who were first treated after 1month of age (26 patients) and those treated before 1month (24 patients). Retrospective chart review was performed for events before 1994, when nitisinone treatment began, and prospective data collection thereafter.
No hospitalizations for acute complications of HT1 occurred during 5731months of nitisinone treatment, versus 184 during 1312months without treatment (p<0.001). Liver transplantation was performed in 20 non-nitisinone-treated patients (71%) at a median age of 26months, versus 7 late-treated patients (26%, p<0.001), and no early-treated patient (p<0.001). No early-treated patient has developed detectable liver disease after more than 5years. Ten deaths occurred in non-nitisinone treated patients versus two in treated patients (p<0.01). Both of the latter deaths were from complications of transplantation unrelated to HT1. One probable nitisinone-related event occurred, transient corneal crystals with photophobia.
Nitisinone treatment abolishes the acute complications of HT1. Some patients with established liver disease before nitisinone treatment eventually require hepatic transplantation. Patients who receive nitisinone treatment before 1month had no detectable liver disease after more than 5years.

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    • "Newborn screening for HT1 is not widely available because of the rarity of HT1 in most areas. However together with early treatment with nitisinone and diet, it is the medical management of choice [11,12]. Recent studies have shown confirmed this [13] Newborn screening is best performed using succinylacetone (SA) as a primary marker because it is sensitive and specific. "
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    ABSTRACT: The management of tyrosinaemia type 1 (HT1, fumarylacetoacetase deficiency) has been revolutionised by the introduction of nitisinone but dietary treatment remains essential and the management is not easy. In this review detailed recommendations for the management are made based on expert opinion, published case reports and investigational studies as the evidence base is limited and there are no prospective controlled studies. The added value of this paper is that it summarises in detail current clinical knowledge about HT1 and makes recommendations for the management.
    Full-text · Article · Jan 2013 · Orphanet Journal of Rare Diseases
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    ABSTRACT: Introduction: Nitisinone has transformed the management of hereditary tyrosinemia type 1 (HT1) and if combined with neonatal screening could abolish most of the clinical manifestations of the disease. Hereditary tyrosinemia type 1 is a rare genetic disease due to fumarylacetoacetase (FAH) deficiency, which usually presents with liver failure. There is a high lifetime risk of developing hepatocellular carcinoma (HCC). The clinical manifestations stem from the cytotoxicity of tyrosine metabolites accumulating proximal to the metabolic defect. Nitisinone acts upstream of the defect to prevent the production of these metabolites. Nitisinone in combination with a tyrosine- and phenylalanine-restricted diet is the standard of care for patients with HT1, with transplantation reserved for where this fails. Where nitisinone is used preemptively, liver disease and HCC appear to be prevented, emphasizing the importance of effective neonatal screening. Treatment should be monitored by ensuring normal growth, close dietary control to maintain amino acid levels in the target range and ensuring nitisinone levels are within the therapeutic range. Nitisinone is well tolerated and has few adverse effects other than a predictable rise in plasma tyrosine levels. It is not currently indicated for routine use post liver transplantation. There are three current unmet concerns in the management of HT1: the lack of universal neonatal screening, the lack of a suitable liquid preparation and neurodevelopmental concerns. Areas covered: This review used a Pubmed search for tyrosinemia and nitisinone as key words and sources available via the EMA website. Expert opinion: The major future challenge is to combine nitisinone use with preemptive diagnosis by universal neonatal screening. The other major challenge in the management of HT1 is the need to understand the cause of the reported neurodevelopmental difficulties. New applications for nitisinone include alkaptonuria.
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