NTBC Treatment Monitoring in Chilean Patients with Tyrosinemia Type 1 and Its Association with Biochemical Parameters and Liver Biomarkers

Treatment and follow-up in Hereditary Tyrosinemia type 1 (HT-1) patients require comprehensive clinical and dietary management, which involves drug therapy with NTBC and the laboratory monitoring of parameters, including NTBC levels, succinylacetone (SA), amino acids, and various biomarkers of liver and kidney function. Good adherence to treatment and optimal adjustment of the NTBC dose, according to clinical manifestations and laboratory parameters, can prevent severe liver complications such as hepatocarcinogenesis (HCC). We analyzed several laboratory parameters for 15 HT-1 patients over one year of follow-up in a cohort that included long-term NTBC-treated patients (more than 20 years), as well as short-term patients (one year). Based on this analysis, we described the overall adherence by our cohort of 70% adherence to drug and dietary treatment. A positive correlation was found between blood and plasma NTBC concentration with a conversion factor of 2.57. Nonetheless, there was no correlation of the NTBC level with SA levels, αFP, liver biomarkers, and amino acids in paired samples analysis. By separating according to the range of the NTBC concentration, we therefore determined the mean concentration of each biochemical marker, for NTBC ranges above 15–25 μmol/L. SA in urine and αFP showed mean levels within controlled parameters in our group of patients. Future studies analyzing a longer follow-up period, as well as SA determination in the blood, are encouraged to confirm the present findings.

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The outcome of seven patients with hereditary tyrosinemia type 1

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2015-0471 ◽

2016 ◽

Vol 29 (10) ◽

Cited By ~ 4

Author(s):

Songul Gokay ◽

Pembe Soylu Ustkoyuncu ◽

Fatih Kardas ◽

Mustafa Kendirci

Keyword(s):

Clinical Symptoms ◽

Age At Onset ◽

Nodule Formation ◽

First Year ◽

Tyrosine Metabolism ◽

Tyrosinemia Type 1 ◽

Hereditary Tyrosinemia ◽

Biochemical Imaging

AbstractBackground:Hereditary tyrosinemia type 1 (HT1) is a rare, inborn error of tyrosine metabolism. It is a fatal disorder without treatment. Early treatment may prevent acute liver failure, renal dysfunction, liver cirrhosis, hepatocellular carcinoma (HCC) and improves survival. The aim of the present study is to describe the clinical, biochemical, imaging and follow-up of seven patients with HT1 and to define the consequences of the late and interrupted treatment.Methods:A retrospective study was carried out with seven HT1 patients.Results:The median age at onset of clinical symptoms was 11.2 months (range, 3–28 months) and the median age at diagnosis was 22 months (range, 6–58 months). Liver enzymes and coagulation parameters were back to normal in all symptomatic patients in about 2 weeks. Alfa-fetoprotein (AFP) levels were normalized within the first year of therapy. Hypoechoic nodule formation was detected in two of the seven patients despite drug treatment without an increase of AFP and any dysplastic changes in the biopsies. One patient died due to metastatic HCC because of the late diagnosis and the poor compliance of the follow-up.Conclusions:This study showed once again that adherence to the treatment and a follow-up schedule of the patients are very important. Also it should not be forgotten that nodule formation can occur despite nitisinone treatment without an increase of AFP. Despite nitisinone treatment, HT1 patients still carry the risk of HCC. HCC must be detected before metastasis to other organs otherwise, patients may lose the chance for liver transplantation.

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Treatment adherence in tyrosinemia type 1 patients

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01879-1 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Domingo González-Lamuño ◽

Paula Sánchez-Pintos ◽

Fernando Andrade ◽

María L. Couce ◽

Luís Aldámiz-Echevarría

Keyword(s):

Treatment Adherence ◽

Positive Reinforcement ◽

Dietary Treatment ◽

Poor Adherence ◽

Blood Levels ◽

Annual Data ◽

Entire Study ◽

Tyrosinemia Type 1 ◽

Hereditary Tyrosinemia

Abstract Background While 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. Results This 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). Conclusions Despite 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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Hereditary tyrosinemia type 1 in children

Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics) ◽

10.21508/1027-4065-2019-64-5-69-83 ◽

2019 ◽

Vol 64 (5) ◽

pp. 69-83

Author(s):

G. V. Volynets ◽

A. V. Nikitin ◽

T. A. Skvortsova

Keyword(s):

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Laboratory Diagnostics ◽

Low Protein ◽

Current State ◽

Tyrosine Metabolism ◽

Tyrosinemia Type 1 ◽

Fumarylacetoacetate Hydrolase ◽

Hereditary Tyrosinemia

Hereditary metabolic disorders include a group of diseases (more than 400) when a defect of a particular gene changes the metabolic process leading either to the accumulation of unwanted metabolites, or to a deficiency of a substance. This group also includes hereditary tyrosinemia type 1, a severe defect of tyrosine metabolism caused by deficiency of fumarylacetoacetate hydrolase (FAH) – the last enzyme of tyrosine catabolic pathway. Tyrosinemia type 1 is an autosomal recessive disorder. This paper presents a review of literature on the current state of diagnosticis and approaches to treatment of tyrosinemia using nitisinone and a low-protein diet, as well as the analysis of clinical manifestations and laboratory diagnostics of hereditary tyrosinemia type 1 in 17 children.

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Heterogeneity of follow-up procedures in French and Belgian patients with treated hereditary tyrosinemia type 1: results of a questionnaire and proposed guidelines

Journal of Inherited Metabolic Disease ◽

10.1007/s10545-011-9429-y ◽

2011 ◽

Vol 35 (5) ◽

pp. 823-829 ◽

Cited By ~ 11

Author(s):

Manuel Schiff ◽

◽

Pierre Broue ◽

Brigitte Chabrol ◽

Corinne De Laet ◽

...

Keyword(s):

Tyrosinemia Type 1 ◽

Hereditary Tyrosinemia

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Monogenic Diabetes: Genetics and Relevance on Diabetes Mellitus Personalized Medicine

Current Diabetes Reviews ◽

10.2174/1573399816666191230114352 ◽

2020 ◽

Vol 16 (8) ◽

pp. 807-819 ◽

Cited By ~ 1

Author(s):

Madalena Sousa ◽

Jácome Bruges-Armas

Keyword(s):

Diabetes Mellitus ◽

Complex Disease ◽

Clinical Manifestations ◽

Neonatal Diabetes ◽

Monogenic Diabetes ◽

Diabetes Genetics ◽

Individualize Treatment

Background: Diabetes mellitus (DM) is a complex disease with significant impression in today's world. Aside from the most common types recognized over the years, such as type 1 diabetes (T1DM) and type 2 diabetes (T2DM), recent studies have emphasized the crucial role of genetics in DM, allowing the distinction of monogenic diabetes. Methods: Authors did a literature search with the purpose of highlighting and clarifying the subtypes of monogenic diabetes, as well as the accredited genetic entities responsible for such phenotypes. Results: The following subtypes were included in this literature review: maturity-onset diabetes of the young (MODY), neonatal diabetes mellitus (NDM) and maternally inherited diabetes and deafness (MIDD). So far, 14 subtypes of MODY have been identified, while three subtypes have been identified in NDM - transient, permanent, and syndromic. Discussion: Despite being estimated to affect approximately 2% of all the T2DM patients in Europe, the exact prevalence of MODY is still unknown, accentuating the need for research focused on biomarkers. Consequently, due to its impact in the course of treatment, follow-up of associated complications, and genetic implications for siblings and offspring of affected individuals, it is imperative to diagnose the monogenic forms of DM accurately. Conclusion: Currently, advances in the genetics field allowed the recognition of new DM subtypes, which until now, were considered slight variations of the typical forms. Thus, it is imperative to act in the close interaction between genetics and clinical manifestations, to facilitate diagnosis and individualize treatment.

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Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation

Genes ◽

10.3390/genes12010003 ◽

2020 ◽

Vol 12 (1) ◽

pp. 3

Author(s):

Haaike Colemonts-Vroninks ◽

Jessie Neuckermans ◽

Lionel Marcelis ◽

Paul Claes ◽

Steven Branson ◽

...

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Liver Regeneration ◽

The Body ◽

Glutathione Metabolism ◽

Short Term ◽

Therapeutic Regime ◽

Tyrosinemia Type 1 ◽

Hereditary Tyrosinemia

Hereditary tyrosinemia type 1 (HT1) is an inherited condition in which the body is unable to break down the amino acid tyrosine due to mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme of the tyrosine degradation pathway. As a consequence, HT1 patients accumulate toxic tyrosine derivatives causing severe liver damage. Since its introduction, the drug nitisinone (NTBC) has offered a life-saving treatment that inhibits the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), thereby preventing production of downstream toxic metabolites. However, HT1 patients under NTBC therapy remain unable to degrade tyrosine. To control the disease and side-effects of the drug, HT1 patients need to take NTBC as an adjunct to a lifelong tyrosine and phenylalanine restricted diet. As a consequence of this strict therapeutic regime, drug compliance issues can arise with significant influence on patient health. In this study, we investigated the molecular impact of short-term NTBC therapy discontinuation on liver tissue of Fah-deficient mice. We found that after seven days of NTBC withdrawal, molecular pathways related to oxidative stress, glutathione metabolism, and liver regeneration were mostly affected. More specifically, NRF2-mediated oxidative stress response and several toxicological gene classes related to reactive oxygen species metabolism were significantly modulated. We observed that the expression of several key glutathione metabolism related genes including Slc7a11 and Ggt1 was highly increased after short-term NTBC therapy deprivation. This stress response was associated with the transcriptional activation of several markers of liver progenitor cells including Atf3, Cyr61, Ddr1, Epcam, Elovl7, and Glis3, indicating a concreted activation of liver regeneration early after NTBC withdrawal.

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