Type 1 tyrosinemia in Finland: a nationwide study

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.

Keywords: Liver transplant; Nitisinone; Screening; Succinylacetone; Tyrosinemia.

Fig. 1

Incidence of type 1 tyrosinemia in 19 Finnish provinces (a) and the family origins of the patients (b)

Fig. 2

Individual blood alpha-fetoprotein (a), tyrosine (b) and nitisinone (c) values of the study patients. Black lines denote nitisinone-treated patients and red lines the values of the liver transplanted patients from diagnosis until the transplantation (star). Grey area denotes the recommended target range

Fig. 3

Changes in individual prothrombin time (a) and phosphate (b), total bilirubin (c) and ammonium ion (d) values in nitisinone-treated study patients

Fig. 4

Changes in individual alanine aminotransferase (a) and gamma-glutamyl transferase (b) values in nitisinone-treated study patients. Red star shows the time of liver transplantation eventually required in one subject