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.

Figure 1

The abnormalities in the pathway of tyrosine metabolism in tyrosinemia type I. Tyrosine is provided both directly from dietary sources and by direct conversion of dietary derived phenylalanine through the activity of phenylalanine hydroxylase (PAH). The catabolic enzymatic activity deficient in tyrosinemia type I (HT-1) is indicated (fumarylacetoacetate hydrolase (FAH)). The abnormally accumulated products due to FAH deficiency are indicated along with their clinical effects. Keratitis is not observed in untreated HT-1 patients but when NTBC therapy is used, it produces elevations of blood tyrosine, which can produce ophthalmologic complications, including keratitis. Succinylacetone is derived from accumulated succinylacetate and is directly associated with renal and neurologic effects (Fanconi renal tubular syndrome, porphyric type crises) and directly inhibits the pathway for heme synthesis at the porphobilinogen synthase activity step. The accumulation of increased levels of δ-aminolevulinic acid is associated with the neurologic (porphyric-like) crises observed in untreated HT-1. Fumarylacetoacetate accumulation is felt to be directly associated with the observed ongoing hepatic and renal damage.

Figure 2

Structure of 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC, nitisinone). mw: molecular weight. IC₅₀: The molar concentration of NTBC that will inhibit 50% of the enzymatic activity of p-OH-phenylpyruvic acid oxidase. T_1/2: The half-life of NTBC concentration in the plasma of healthy young adults.