Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations

Abstract

Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems and long term risks for hepatocellular carcinoma. An effective medical treatment with 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC) exists but requires early identification of affected children for optimal long-term results. Newborn screening (NBS) utilizing blood succinylacetone as the NBS marker is superior to observing tyrosine levels as a way of identifying neonates with HT-1. If identified early and treated appropriately, the majority of affected infants can remain asymptomatic. A clinical management scheme is needed for infants with HT-1 identified by NBS or clinical symptoms. To this end, a group of 11 clinical practitioners, including eight biochemical genetics physicians, two metabolic dietitian nutritionists, and a clinical psychologist, from the United States and Canada, with experience in providing care for patients with HT-1, initiated an evidence- and consensus-based process to establish uniform recommendations for identification and treatment of HT-1. Recommendations were developed from a literature review, practitioner management survey, and nominal group process involving two face-to-face meetings. There was strong consensus in favor of NBS for HT-1, using blood succinylacetone as a marker, followed by diagnostic confirmation and early treatment with NTBC and diet. Consensus recommendations for both immediate and long-term clinical follow-up of positive diagnoses via both newborn screening and clinical symptomatic presentation are provided.

Mutational spectrum of Mexican patients with tyrosinemia type 1: In silico modeling and predicted pathogenic effect of a novel missense FAH variant

“…The high proportion of hepatocellular carcinoma observed in our patients (5/8, 62.5%) is within the incidence previously reported for this complication in nontreated or late‐treated patients (14%–75%) (Khanna & Verma, ). A conclusive explanation for the hepatocellular carcinoma pathogenesis in HT1 has not been established, it is known that fumarylacetoacetate, maleylacetoacetate, and SA form glutathione adducts that can promote free radical damage of hepatocytes and susceptibility to genotoxicity (Chinsky et al, ). Furthermore, fumarylacetoacetate inhibits DNA glycosylases, which play a role in the repair of mutagenic oxidative base lesions in DNA, (Bliksrud, Ellingsen, & Bjørås, ) and explains the high incidence of hepatocellular carcinoma seen in HT1 patients.…”

Living‐donor liver transplantation for children with tyrosinemia type I

“…All patients had been confirmed as tyrosinemia type I before being referred to our hospital and the definitive diagnosis was established based on the following criteria: (a) the identification of biallelic pathogenic mutations in FAH through genetic test; (b) characteristic biochemical findings including increased plasma and urinary SA and the elevated plasma concentrations of tyrosine, methionine and phenylalanine, as well as tyrosine metabolites; and (c) clinical features such as severe liver disease, signs of renal disease, rickets and neurological crises …”

Clinical Features of 29 Patients with Hereditary Tyrosinemia I in Western Turkey

“…In follow up, regular abdominal USG was performed every 6-12 months and AFP levels, plasma amino acids and urine succinylacetone were checked every 3 months. Chinsky et al (27) recommended follow-up with USG or computed tomography or magnetic resonance imaging of the liver yearly and monitoring of AFP levels every 3-6 months. Liver enzymes and coagulation (27).…”

“…Chinsky et al (27) recommended follow-up with USG or computed tomography or magnetic resonance imaging of the liver yearly and monitoring of AFP levels every 3-6 months. Liver enzymes and coagulation (27). Eleven patients underwent liver transplantation, all living donor transplantations (Table III).…”