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

Abstract

Background: Hepatorenal 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.

Methods: Via 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.

Results: Early 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).

Conclusion: Based 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.

Figure 1

Tyrosine metabolism.

Figure 2

Distribution of patients according to diagnostic procedure.

Figure 3

Initial symptoms are age-dependent. a-i: Age-dependency of initial symptoms: The most common symptoms like renal tubular dysfunction, nephromegaly, growth retardation, rickets, liver dysfunction and carcinoma and the combination of symptoms are depicted. *significant difference (p <0.05) vs < 2 months. n: <2 m =34 patients, 2-6 m = 43 patients, >6 m =61 patients.

Figure 4

The frequency of complications depends on the age at start of NTBC-treatment. a-g: Age at initiation of NTBC treatment and frequency of complications: The most common complications like liver disease, HCC,renal dysfunction, rickets and necessity of liver transplantation are shown. *significant difference (p <0.05) vs < 1 month. n: < 1 m =37 patients; 1-6 m =45 patients; 7-12 m =20 patients; >13 m =46 patients.

Figure 5

Differences in dietary treatment. Phe = Phenylalanine; Tyr = Tyrosine.