Type 1 tyrosinemia in Finland: a nationwide study.

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.

First Scandinavian case of successful pregnancy during nitisinone treatment for type 1 tyrosinemia.

Background Type 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 presentation A 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. Conclusions Pregnancy 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.

Prevalence and associated factors of abnormal liver values in children with celiac disease.

BACKGROUND: The prevalence and factors associated with transaminasemia in celiac disease are poorly known. AIMS: To investigate these issues in paediatric celiac patients and controls. METHODS: Alanine aminotransferase (ALT) was studied in 150 children with untreated celiac disease, 161 disease controls and 500 population-based controls. The association between ALT and clinical and histological variables and the effect of a gluten-free diet were investigated in celiac patients. RESULTS: ALT was >30U/l: celiac disease 14.7%, ulcerative colitis 37.2%, Crohn's disease 16.7%, reflux disease 16.2%, functional gastrointestinal symptoms 8.9%, and controls 3.6%. Factors associated with increased ALT were poor growth (45.5% vs 24.2%, P=0.039) and severe villous atrophy (median 23.0U/l vs partial atrophy 19.0U/l, P=0.008), but not age, sex, body-mass index, type or severity of symptoms and co-morbidities. ALT had a moderate correlation with endomysial (r=0.334, P<0.001) and transglutaminase antibodies (r=0.264, P=0.002) and ferritin (r=-0.225, P=0.03), but not with other laboratory values. On gluten-free diet median ALT decreased from 22.0U/l to 18.0U/l (P=0.002) and 80% of the high values normalized. CONCLUSION: Increased ALT is associated with more advanced serological and histological celiac disease. Adherence to a gluten-free diet appears to result in normalization or reduction of ALT levels.