Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice

Abstract

BackgroundHepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data.MethodsVia questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications.ResultsEarly treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 μM) and NTBC-levels in the therapeutic range (20–40 μM). Side effects of NTBC are mild and often transient.Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood).ConclusionBased on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.

Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria

“…High serum concentrations of tyrosine are known to cause eye lesions in some patients due to high concentrations in the aqueous humor (Hanhart 1947;Lock et al 2014). In the treatment of HT-1 with nitisinone, it is therefore recommended that serum tyrosine be kept below 400-500 mmol/L, by using a diet low in tyrosine and phenylalanine (Mayorandan et al 2014; SmPC for Orfadin). Even the lowest dose in our study, 1 mg daily, resulted in tyrosine levels above this limit in every patient, indicating that diet restrictions may be required also if treating AKU patients with nitisinone, at least if such patients would develop eye symptoms due to tyrosinemia.…”

Chronic Phenotype Characterization of a Large-Animal Model of Hereditary Tyrosinemia Type 1

“…14,22 In humans, treatment with NTBC abolishes the acute complications of HT1 in most patients. 23 In this study, we characterized the influence of dosage of NTBC on the chronic phenotype of HT1 in FAH À/À pigs. Based on previous observations, 1 mg/kg per day NTBC was administered to all pigs during the first 30 days to prevent perinatal morbidity and mortality.…”

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

“…Implementation in neonatal blood spot screening (NBS) and treatment with 2-(2-nitro-4-trifluoromethyl-benzyl)-1,3-cyclohexanedione (NTBC) to prevent accumulation of toxic metabolites by inhibiting tyrosine catabolism upstream from the primary enzymatic defect has largely improved clinical outcome (Larochelle et al 2012;Mayorandan et al 2014).…”