Type 1 tyrosinemia in Finland: a nationwide study

Linnea Äärelä,Tea Soini,Laura Kivelä,Kalle Kurppa,Nina Vuorela,Heini Huhtala,Pasi I Nevalainen,Pauliina Hiltunen,Markku Heikinheimo

doi:10.1186/s13023-020-01547-w

Abstract

BackgroundIntroduction 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.ResultsType 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.ConclusionsPrognosis 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.

Highlights

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
Three families had a history of Type 1 tyrosinemia (TT1)
We found the incidence of TT1 to be 1/90,102 in Finland, with a significant enrichment (1/9,990) in South Ostrobothnia

Summary

Introduction

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. 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. Tyrosinemia is an autosomal recessively inherited metabolic disease presenting with three clinically distinct subtypes. The majority of patients have type I tyrosinemia (TT1, OMIM 276,700), types II and III being extremely rare [1,2,3]. Typical presentation includes liver failure and kidney tubular dysfunction, other reported findings being, for example, growth failure, rickets and pseudo-porphyric crises [6, 9,10,11,12]. Untreated TT1 increases the risk for liver carcinoma [12, 13]

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Conclusion