芬兰 1 型酪氨酸血症：一项全国性研究。
Type 1 tyrosinemia in Finland: a nationwide study.
机构信息
Center for Child Health Research, Tampere University, Tampere, Finland.
Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
出版信息
Orphanet J Rare Dis. 2020 Oct 12;15(1):281. doi: 10.1186/s13023-020-01547-w.
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.
背景
尼替西农的引入和新生儿筛查（NBS）改变了 1 型酪氨酸血症的治疗方式，但这些变化对长期结果的影响仍不清楚。此外，对于后期并发症的预测因素、药物水平的意义以及实验室和影像学发现的正常化仍知之甚少。我们在一项全国性研究中调查了这些问题。
结果
1978 年至 2019 年间，芬兰共诊断出 22 例 1 型酪氨酸血症患儿。发病率为 1/90102，南奥斯特罗波西亚（1/9990）明显富集。中位诊断年龄为 5 个月（范围 0.5-36 个月），55%为女孩，13 例为 Trp262X 突变纯合子。4 例通过筛查发现，18 例通过临床发现，其主要发现为肝功能衰竭（分别为 50%和 100%，p=0.026）、腹水（分别为 0%和 53%，p=0.104）、肾小管病（分别为 0%和 65%，p=0.035）、佝偻病（分别为 25%和 65%，p=0.272）、生长发育不良（分别为 0%和 66%，p=0.029）、血小板减少症（分别为 25%和 88%，p=0.028）和贫血（分别为 0%和 47%，p=0.131）。1 例患者接受饮食治疗，7 例患者接受移植治疗，14 例患者接受尼替西农治疗。3 例后期诊断（6-33 个月）的尼替西农治疗患者后来需要进行移植。移植组肾功能不全（86%和 7%，p=0.001）、高血压（57%和 7%，p=0.025）和骨质疏松/骨密度降低（71%和 14%，p=0.017）的发生率高于尼替西农治疗组。除 1 例患者因肝内肝细胞癌外，所有患者的尼替西农治疗后血液/血清甲胎蛋白迅速下降。31 个月时肝功能值恢复正常，18 个月时除血小板减少症外其他实验室值恢复正常。3-56 个月时影像学表现恢复正常，5 例肝脾异常患者除外。尽管尿琥珀酰丙酮无法检测到，但较低的尼替西农平均浓度与严重并发症的高风险相关（r=0.758，p=0.003）。
结论
在尼替西农时代，1 型酪氨酸血症的预后有所改善，NBS 似乎提供了进一步的益处。然而，长期并发症的风险仍然存在，尤其是在晚期诊断和/或尼替西农水平不足的情况下。
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