Overview of European Practices for Management of Tyrosinemia Type 1: Towards European Guidelines

Abstract

The introduction of nitisinone (NTBC) and newborn screening for Tyrosinemia type 1 (TT1) enabled preemptive treatment of patients, thereby significantly improving outcomes by preventing liver, kidney, and neurological issues. Treatment goals have shifted from emergency treatment to long-term care. To evaluate the risk of developing complications with aging, due to TT1 itself or its treatment, long-term follow-up is essential. In 2014, an overview of TT1 management practices in Europe was published. Within the Metabolic European Reference Network's subnetwork on amino-and-organic acidurias (MetabERN-AOA), we considered it important to give an update on current TT1 management practices in Europe. An online survey study was performed among members of the MetabERN-AOA subnetwork, and participants of a workshop on TT1 at the European Metabolic Group Meeting of Nutricia. Findings were compared to existing data from the aforementioned publication from 2014 and previously published recommendations. Thirty-two centers (16 European countries) completed the survey. Both consistencies and inconsistencies in TT1 management were seen. Inconsistencies were observed in the frequency and methods of follow-up, dosing of NTBC, and target ranges of biochemical markers. Compared to 2014, key differences included an increased number of patients detected by newborn screening, lower NTBC dosing, and a shift from interest in mainly hepatic to hepatic and neurocognitive outcomes. These results align with trends seen in TT1 recommendations over the years. In addition to numerous consistencies, many aspects in TT1 management still differ widely across Europe, suggesting the need for uniform guidance in clinical management beyond existing recommendations.

Keywords: NTBC; guidelines; management; tyrosinemia type 1.

FIGURE 1

Responses per country; Dark green indicate countries with newborn screening for Tyrosinemia type I and light green indicate countries without newborn screening for tyrosinemia Type I.

FIGURE 2

Number of out‐patient visits: Y‐axes: Absolute number of times an answer was given, X‐axes: Frequency of out‐patient visits in absolute numbers. (A) Number of visits during the first month of life, (B–F) number of visits per year for different age groups from 1 month to adulthood, and during pregnancy. Number of responses can differ (e.g., 25 in A and 28 in D) depending on which kind of patients physicians treat, for example child physician, adult physician or both.

FIGURE 3

Dosing of NTBC. (A) NTBC dose after initial diagnosis (both clinical and through NBS), and maintenance dose. Pie‐charts divide absolute number of responses. (B) Methods for optimization of NTBC dosage. 5‐ALA, 5‐aminolevulinic acid; AFP, alpha fetoprotein; NA, not applicable; PSA, porphobilinogen synthase activity; X‐axis, number of times an answer was chosen in absolute numbers; Y‐axis, item possibly important for optimizing NTBC dosing.

FIGURE 4

Suboptimal dosing and adverse effects of NTBC. (A) Clinical signs of suboptimal NTBC dosage according to responders. (B) Biochemical signs of suboptimal NTBC treatment according to responders. (C) Adverse effects of NTBC encountered by responders. X‐axes: Absolute number of times an answer was given for each specific item on the y‐axis. Multiple answers from one participant were allowed.

FIGURE 5

Metabolic monitoring in TT1. (A) Overview of biochemical markers frequently monitored in TT1patients according to responders. (B) Preferred matrices for the monitored markers according to responders. Pie charts divide absolute number of responses. (C) Target values for different markers. X‐axes (A+C): Absolute number of times an answer was chosen. 5‐ALA, 5‐aminolevulinic acid; AFP, alpha fetoprotein; PSA, porphobilinogen synthase activity. * indicates multiple answers per participant allowed.

FIGURE 6

Frequency of metabolic monitoring in TT1 in different age groups. Y‐axes: frequency of monitoring, X‐axes: Absolute number of times an answer was chosen. (A) Frequency of monitoring in patients < 4 years old. (B) In case of different frequencies depending on age, frequency of monitoring > 4 years old. X‐axes: number of times answer was chosen. * Example: 1–3/3 months meaning 1–3 times per 3 months.