No abstract

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.

BackgroundType 1 tyrosinemia is a hereditary metabolic disease in which tyrosine metabolites damage the liver and kidneys. Nitisinone medication revolutionized the treatment, but the effects of the drug during human pregnancy are unknown.Case presentationA 17-year-old tyrosinemia patient became pregnant. Nitisinone was continued throughout pregnancy with a varying serum concentration and dose ranging from 0.8 to 1.4 mg/kg/day. Blood tyrosine remained stable until it increased in late pregnancy. α-fetoprotein increased to 284 μg/L without new changes in liver. Urine succinylacetone remained undetectable, but there were signs of possibly reoccurring kidney tubulopathy. Fetal ultrasound monitoring was normal throughout the pregnancy and the newborn healthy. After the delivery, α-fetoprotein normalized, but tyrosine continued to rise for up to 1 year. The child is developing normally.ConclusionsPregnancy during nitisinone was successful, but tailoring of the drug dose and possibly reappearing complications, as also increasing serum tyrosine concentration after delivery warranted intensified surveillance.

Abstract 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 (1/9,990). 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 median 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.

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 (1/9,990). 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.