Nitisinone和新生儿筛查(NBS)的引入改变了1型酪氨酸血症的治疗方法,但是这些变化对长期结果的影响仍然模糊。此外,后期并发症的预测因素,药物水平的重要性以及实验室和影像学检查结果的正常化知之甚少.我们在一项全国性的研究中调查了这些问题。
1978-2019年,芬兰22名儿童被诊断出1型酪氨酸血症。发病率为1/90,102,在南Ostrobothnia中有显着富集(1/9990)。诊断时的中位年龄为5(范围0.5-36)个月,55%为女孩,13例具有纯合子Trp262X突变。通过筛查检测出4例,临床检测出18例,他们的主要发现是肝功能衰竭(50%vs.100%,分别,p=0.026),腹水(0%vs.53%,p=0.104),肾小管病(0%vs.65%,p=0.035),病(25%vs.65%,p=0.272),增长失败(0%与66%,p=0.029),血小板减少症(25%vs.88%,p=0.028)和贫血(0%vs.47%,p=0.131)。一名患者接受了饮食治疗,7例移植和14例尼替辛酮移植。三名晚期诊断(6-33个月)尼替辛酮治疗的患者后来需要移植。肾功能障碍(86%vs.7%,p=0.001),高血压(57%vs.7%,p=0.025)和骨质减少/骨质疏松症(71%vs.14%,p=0.017)在移植中比尼替辛酮治疗的患者更频繁。除一名患者外,尼替辛酮的血液/血清甲胎蛋白迅速下降,后来发展为肝内肝细胞癌。肝值在31个月内恢复正常,其他实验室值在18个月内除了血小板减少。影像学检查结果在3-56个月内恢复正常,不包括5例肝或脾异常患者。尽管无法检测到尿液中的琥珀酰丙酮,但低平均尼替辛酮浓度与严重并发症的高风险相关(r=0.758,p=0.003)。
在使用尼替辛酮的时代,1型酪氨酸血症的预后有所改善,国家统计局似乎提供了进一步的好处。然而,并发症的长期风险仍然存在,特别是在晚期诊断和/或Nitisinone水平不足的情况下。
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.
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.
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.