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Type 1 tyrosinemia in Finland: a nationwide study

BACKGROUND: Introduction of nitisinone and newborn screening (NBS) have transformed the treatment of type 1 tyrosinemia, but the effects of these changes on the long-term outcomes remain obscure. Also, the predictors for later complications, the significance of drug levels and the normalization of l...

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Autores principales: Äärelä, Linnea, Hiltunen, Pauliina, Soini, Tea, Vuorela, Nina, Huhtala, Heini, Nevalainen, Pasi I., Heikinheimo, Markku, Kivelä, Laura, Kurppa, Kalle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549233/
https://www.ncbi.nlm.nih.gov/pubmed/33046095
http://dx.doi.org/10.1186/s13023-020-01547-w
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author Äärelä, Linnea
Hiltunen, Pauliina
Soini, Tea
Vuorela, Nina
Huhtala, Heini
Nevalainen, Pasi I.
Heikinheimo, Markku
Kivelä, Laura
Kurppa, Kalle
author_facet Äärelä, Linnea
Hiltunen, Pauliina
Soini, Tea
Vuorela, Nina
Huhtala, Heini
Nevalainen, Pasi I.
Heikinheimo, Markku
Kivelä, Laura
Kurppa, Kalle
author_sort Äärelä, Linnea
collection PubMed
description BACKGROUND: Introduction of nitisinone and newborn screening (NBS) have transformed the treatment of type 1 tyrosinemia, but the effects of these changes on the long-term outcomes remain obscure. Also, the predictors for later complications, the significance of drug levels and the normalization of laboratory and imaging findings are poorly known. We investigated these issues in a nationwide study. RESULTS: Type 1 tyrosinemia was diagnosed in 22 children in 1978–2019 in Finland. Incidence was 1/90,102, with a significant enrichment in South Ostrobothnia (1/9990). Median age at diagnosis was 5 (range 0.5–36) months, 55% were girls and 13 had homozygotic Trp262X mutation. Four patients were detected through screening and 18 clinically, their main findings being liver failure (50% vs. 100%, respectively, p = 0.026), ascites (0% vs. 53%, p = 0.104), renal tubulopathy (0% vs. 65%, p = 0.035), rickets (25% vs. 65%, p = 0.272), growth failure (0% vs. 66%, p = 0.029), thrombocytopenia (25% vs. 88%, p = 0.028) and anaemia (0% vs. 47%, p = 0.131). One patient was treated with diet, seven with transplantation and 14 with nitisinone. Three late-diagnosed (6–33 months) nitisinone treated patients needed transplantation later. Kidney dysfunction (86% vs. 7%, p = 0.001), hypertension (57% vs. 7%, p = 0.025) and osteopenia/osteoporosis (71% vs. 14%, p = 0.017) were more frequent in transplanted than nitisinone-treated patients. Blood/serum alpha-fetoprotein decreased rapidly on nitisinone in all but one patient, who later developed intrahepatic hepatocellular carcinoma. Liver values normalized in 31 months and other laboratory values except thrombocytopenia within 18 months. Imaging findings normalized in 3–56 months excluding five patients with liver or splenic abnormalities. Low mean nitisinone concentration was associated with higher risk of severe complications (r = 0.758, p = 0.003) despite undetectable urine succinylacetone. CONCLUSIONS: Prognosis of type 1 tyrosinemia has improved in the era of nitisinone, and NBS seems to provide further benefits. Nevertheless, the long-term risk for complications remains, particularly in the case of late diagnosis and/or insufficient nitisinone levels.
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spelling pubmed-75492332020-10-13 Type 1 tyrosinemia in Finland: a nationwide study Äärelä, Linnea Hiltunen, Pauliina Soini, Tea Vuorela, Nina Huhtala, Heini Nevalainen, Pasi I. Heikinheimo, Markku Kivelä, Laura Kurppa, Kalle Orphanet J Rare Dis Research BACKGROUND: Introduction of nitisinone and newborn screening (NBS) have transformed the treatment of type 1 tyrosinemia, but the effects of these changes on the long-term outcomes remain obscure. Also, the predictors for later complications, the significance of drug levels and the normalization of laboratory and imaging findings are poorly known. We investigated these issues in a nationwide study. RESULTS: Type 1 tyrosinemia was diagnosed in 22 children in 1978–2019 in Finland. Incidence was 1/90,102, with a significant enrichment in South Ostrobothnia (1/9990). Median age at diagnosis was 5 (range 0.5–36) months, 55% were girls and 13 had homozygotic Trp262X mutation. Four patients were detected through screening and 18 clinically, their main findings being liver failure (50% vs. 100%, respectively, p = 0.026), ascites (0% vs. 53%, p = 0.104), renal tubulopathy (0% vs. 65%, p = 0.035), rickets (25% vs. 65%, p = 0.272), growth failure (0% vs. 66%, p = 0.029), thrombocytopenia (25% vs. 88%, p = 0.028) and anaemia (0% vs. 47%, p = 0.131). One patient was treated with diet, seven with transplantation and 14 with nitisinone. Three late-diagnosed (6–33 months) nitisinone treated patients needed transplantation later. Kidney dysfunction (86% vs. 7%, p = 0.001), hypertension (57% vs. 7%, p = 0.025) and osteopenia/osteoporosis (71% vs. 14%, p = 0.017) were more frequent in transplanted than nitisinone-treated patients. Blood/serum alpha-fetoprotein decreased rapidly on nitisinone in all but one patient, who later developed intrahepatic hepatocellular carcinoma. Liver values normalized in 31 months and other laboratory values except thrombocytopenia within 18 months. Imaging findings normalized in 3–56 months excluding five patients with liver or splenic abnormalities. Low mean nitisinone concentration was associated with higher risk of severe complications (r = 0.758, p = 0.003) despite undetectable urine succinylacetone. CONCLUSIONS: Prognosis of type 1 tyrosinemia has improved in the era of nitisinone, and NBS seems to provide further benefits. Nevertheless, the long-term risk for complications remains, particularly in the case of late diagnosis and/or insufficient nitisinone levels. BioMed Central 2020-10-12 /pmc/articles/PMC7549233/ /pubmed/33046095 http://dx.doi.org/10.1186/s13023-020-01547-w Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Äärelä, Linnea
Hiltunen, Pauliina
Soini, Tea
Vuorela, Nina
Huhtala, Heini
Nevalainen, Pasi I.
Heikinheimo, Markku
Kivelä, Laura
Kurppa, Kalle
Type 1 tyrosinemia in Finland: a nationwide study
title Type 1 tyrosinemia in Finland: a nationwide study
title_full Type 1 tyrosinemia in Finland: a nationwide study
title_fullStr Type 1 tyrosinemia in Finland: a nationwide study
title_full_unstemmed Type 1 tyrosinemia in Finland: a nationwide study
title_short Type 1 tyrosinemia in Finland: a nationwide study
title_sort type 1 tyrosinemia in finland: a nationwide study
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549233/
https://www.ncbi.nlm.nih.gov/pubmed/33046095
http://dx.doi.org/10.1186/s13023-020-01547-w
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