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Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain.

ABSTRACT: Treatment with nitisinone (NTBC) has brought about a drastic improvement in the treatment and prognosis of hereditary tyrosinemia type I (HT1). We conducted a retrospective observational multicentric study in Spanish HT1 patients treated with NTBC to assess clinical and biochemical long-term evolution.We evaluated 52 patients, 7 adults and 45 children, treated with NTBC considering: age at diagnosis, diagnosis by clinical symptoms, or by newborn screening (NBS); phenotype (acute/subacute/chronic), mutational analysis; symptoms at diagnosis and clinical course; biochemical markers; doses of NTBC; treatment adherence; anthropometric evolution; and neurocognitive outcome.The average follow-up period was 6.1?±?4.9 and 10.6?±?5.4 years in patients with early and late diagnosis respectively. All patients received NTBC from diagnosis with an average dose of 0.82?mg/kg/d. All NBS-patients (n?=?8) were asymptomatic at diagnosis except 1 case with acute liver failure, and all remain free of liver and renal disease in follow-up. Liver and renal affectation was markedly more frequent at diagnosis in patients with late diagnosis (P?T.After NTBC treatment a reduction in tyrosine and alpha-fetoprotein levels was observed in all the study groups, significant for alpha-fetoprotein in no NBS-group (P?=?.03), especially in subacute/chronic forms (P?=?.018).This series confirms that NTBC treatment had clearly improved the prognosis and quality of life of HT1 patients, but it also shows frequent cognitive dysfunctions and learning difficulties in medium-term follow-up, and, in a novel way, a high percentage of overweight/obesity.

SUBMITTER: Couce ML

PROVIDER: S-EPMC6775438 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain.

Couce María Luz ML Sánchez-Pintos Paula P Aldámiz-Echevarría Luís L Vitoria Isidro I Navas Victor V Martín-Hernández Elena E García-Volpe Camila C Pintos Guillem G Peña-Quintana Luis L Hernández Tomás T Gil David D Sánchez-Valverde Félix F Bueno María M Roca Iria I López-Ruzafa Encarna E Díaz-Fernández Carmen C

Medicine 20190901 39

Treatment with nitisinone (NTBC) has brought about a drastic improvement in the treatment and prognosis of hereditary tyrosinemia type I (HT1). We conducted a retrospective observational multicentric study in Spanish HT1 patients treated with NTBC to assess clinical and biochemical long-term evolution.We evaluated 52 patients, 7 adults and 45 children, treated with NTBC considering: age at diagnosis, diagnosis by clinical symptoms, or by newborn screening (NBS); phenotype (acute/subacute/chronic ...[more]

PMID: 31574857

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Project description:Hereditary tyrosinemia type 1 (HT1) is a genetic disorder of the tyrosine degradation pathway (TIMD) with unmet therapeutic needs. HT1 patients are unable to fully break down the amino acid tyrosine due to a deficient fumarylacetoacetate hydrolase (FAH) enzyme and, therefore, accumulate toxic tyrosine intermediates. If left untreated, they experience hepatic failure with comorbidities involving the renal and neurological system and the development of hepatocellular carcinoma (HCC). Nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, rescues HT1 patients from severe illness and death. However, despite its demonstrated benefits, HT1 patients under continuous NTBC therapy are at risk to develop HCC and adverse reactions in the eye, blood and lymphatic system, the mechanism of which is poorly understood. Moreover, NTBC does not restore the enzymatic defects inflicted by the disease nor does it cure HT1. Here, the changes in molecular pathways associated to the development and progression of HT1-driven liver disease that remains uncorrected under NTBC therapy were investigated using whole transcriptome analyses on the livers of Fah- and Hgd-deficient mice under continuous NTBC therapy and after seven days of NTBC therapy discontinuation. Alkaptonuria (AKU) was used as a tyrosine-inherited metabolic disorder reference disease with non-hepatic manifestations. The differentially expressed genes were enriched in toxicological gene classes related to liver disease, liver damage, liver regeneration and liver cancer, in particular HCC. Most importantly, a set of 25 genes related to liver disease and HCC development was identified that was differentially regulated in HT1 vs. AKU mouse livers under NTBC therapy. Some of those were further modulated upon NTBC therapy discontinuation in HT1 but not in AKU livers. Altogether, our data indicate that NTBC therapy does not completely resolves HT1-driven liver disease and supports the sustained risk to develop HCC over time as different HCC markers, including Moxd1, Saa, Mt, Dbp and Cxcl1, were significantly increased under NTBC.

Project description:BACKGROUND:Tyrosinemia type 1 (TYR1) is a rare autosomal recessive disorder of amino acid metabolism that is fatal without treatment. With medication (nitisinone) and dietary restrictions outcomes are improved. We conducted a systematic review to investigate if treatment with nitisinone following screening provides better long-term outcomes than treatment with nitisinone following symptomatic detection. METHODS:We searched Web of Science, Medline, Pre-Medline, and Embase up to 23rd September 2016 for journal articles comparing clinical outcomes of TYR1 patients receiving earlier versus later nitisinone treatment. Two reviewers independently screened titles and abstracts, assessed full texts, and appraised study quality. Data extraction was performed by a single reviewer and checked by a second. RESULTS:We included seven articles out of 470 unique records identified by our search. The seven articles included four studies (three cohort studies and one cross-sectional study). Study sample sizes ranged from 17 to 148. There is consistent evidence that nitisinone is an effective treatment for TYR1, and some evidence that earlier treatment with nitisinone and dietary restrictions within the first one or 2 months of life is associated with reduced need for liver transplantation, lower rates of renal dysfunction, fewer neurological crises, and fewer, shorter hospital admissions compared to later treatment. However, study quality was moderate to weak, with high risk of confounding and applicability concerns to the screening context. We conducted post hoc analyses to address these issues. Results suggested an association between earlier treatment and fewer liver transplants (earlier treatment: 0% of 10-24 patients; later treatment: 25-60% of 4-15 patients), but no impact on neurological crises. We found no effect of treatment timing on mortality in either the primary or post hoc analyses. Post hoc analyses of other health-related outcomes were not possible because of sample size or reporting. CONCLUSIONS:There is some evidence from observational studies that earlier treatment with nitisinone might be beneficial but this is subject to bias. The applicability of our findings to the screening context or clinical practice is limited as not all early-treated patients were identified by screening and late-treated groups included patients born prior to the availability of nitisinone.

Project description:Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone-treated AKU mice, and in an observational study of dietary intervention in AKU patients. Nitisinone-treated AKU mice were fed tyrosine/phenylalanine-free and phenylalanine-free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre-nitisinone, post-nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700??mol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine-free amino acid supplements. Elevated tyrosine (813??mol/L) was significantly reduced in nitisinone-treated AKU mice fed a tyrosine/phenylalanine-free diet in a dose responsive manner. At 3?days of restriction, tyrosine was 389.3, 274.8, and 144.3 ?mol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine-free diet; at 3?days tyrosine was 757.3, 530.2, and 656.2 ?mol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (P =?.002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine-free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700??mol/L. Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone-induced tyrosinemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients.

Project description:BackgroundWhile therapeutic advances have significantly improved the prognosis of patients with hereditary tyrosinemia type 1 (HT1), adherence to dietary and pharmacological treatments is essential for an optimal clinical outcome. Poor treatment adherence is well documented among patients with chronic diseases, but data from HT1 patients are scarce. This study evaluated pharmacological and dietary adherence in HT1 patients both directly, by quantifying blood levels nitisinone (NTBC) levels and metabolic biomarkers of HT1 [tyrosine (Tyr), phenylalanine (Phe), and succinylacetone]; and indirectly, by analyzing NTBC prescriptions from hospital pharmacies and via clinical interviews including the Haynes-Sackett (or self-compliance) test and the adapted Battle test of patient knowledge of the disease.ResultsThis observational study analyzed data collected over 4 years from 69 HT1 patients (7 adults and 62 children; age range, 7 months-35 years) who were treated with NTBC and a low-Tyr, low-Phe diet. Adherence to both pharmacological and, in particular, dietary treatment was poor. Annual data showed that NTBC levels were lower than recommended in more than one third of patients, and that initial Tyr levels were high (> 400 µM) in 54.2-64.4% of patients and exceeded 750 µM in 25.8% of them. Remarkably, annual normalization of NTBC levels was observed in 29.4-57.9% of patients for whom serial NTBC determinations were performed. Poor adherence to dietary treatment was more refractory to positive reinforcement: 36.2% of patients in the group who underwent multiple analyses per year maintained high Tyr levels during the entire study period, and, when considering each of the years individually this percentage ranged from 75 to 100% of them. Indirect methods revealed percentages of non-adherent patients of 7.3 and 15.9% (adapted Battle and Haynes tests, respectively).ConclusionsDespite initially poor adherence to pharmacological and especially dietary treatment among HT1 patients, positive reinforcement at medical consultations resulted in a marked improvement in NTBC levels, indicating the importance of systematic positive reinforcement at medical visits.

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Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain.

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Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain.

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