Januari 2012
26
6
Tyrosinemia Type 1 – Latest Evidence
This part of the document will be changed in the first revision, in which the level of evidence will
be displayed throughout this care pathway.
Tyrosinemia Type 1
Tyrosinemia type 1 (MIM 276700) results from a deficiency of fumarylacetoacetate hydrolase
(
FAH; EC 3.7.1.2).
1
Decreased FAH activity leads to accumulation of the tyrosine pathway
metabolites fumarylacetoacetate (FAA), maleyacetoacetate (MAA) and succinylacetoacetate (SAA).
SAA is converted to succinylacetone (SA), which leads to inhibition of other hepatic enzymes
(
including PBG-synthase and subsequently δ-ALA dehydratase). The FAH-enzyme is expressed
mainly in the liver and kidneys, therefore pathologic changes occur predominantly in these
organs.
2
The underlying defect is a mutation in the gene for FAH, inherited in an autosomal
recessive manner. The overall incidence is 1 in 100.000-120.000.
3
Untreated tyrosinemia type 1 present either in very young infants (infantile or very early type
presenting before 2 months of age) with severe liver involvement, from abnormal blood
coagulation and modestly elevated transaminases and bilirubin, progressing to liver failure with
ascites and (gastrointestinal) bleeding, while tubulopathie may also be an important cause of
clinical entity at this age. These patients are at risk for early death and some 10% does not respond
well enough to NTBC to prevent from the need of liver transplantation. There is a subset of
patients that present with comparable features but between 2-6 months of age (early type).
4
These patients usually respond well to NTBC. Patients presenting after 6 months of age present
quite different (late presenting type) with either liver dysfunction and/or significant renal tubular
dysfunction (aminoaciduria, phosphate loss and renal tubular acidosis) especially presenting as
hypophosphatemic rickets or failure to thrive. They however may also present as hypoglycaemia,
cardiomyopathy, neurologic crisis similar to acute intermittent porphyria, with changed mental
status, abdominal pain, and especially peripheral neuropathy (Guillian Barre), as well as slow
development due to chronic peripheral neuropathy and/or large abdomen with liver involvement.
4
The prognosis was related to age at presentation and clinical phenotype, varying from < 40% to
96%
first year survival after diagnosis. Late outcome was especially influenced by the risk of
hepatocellular carcinoma, that remain there all their life.
5
With new treatment options (liver
transplantation, NTBC and diet) the current outcome has been drastically improved. Treatment
with NTBC and low-tyrosine diet has resulted in a >90% overall survival rate, normal growth,
improved liver function, prevention of cirrhosis, correction of renal tubular acidosis and
improvement in secondary rickets.
6-8
Now, the outcome is different. The earlier the presentation, and the earlier NTBC can be started,
the better the outcome seems to be, especially with regard to the risk of hepatocellular carcinoma
(
van Spronsen 2007). Therefore, neonatal screening is very important. Neonatal screening was
introduced in the Netherlands in October 2008 by measuring the blood spot succinylacetone
levels, with a cut-off value of currently 1.2 μmol/L.
Treatment
NTBC (Nitisinon; 2-(2-nitro-4-trifluoromethylbenonlyzoyl)-1,3-cyclohexanedione)
Nitisinon is an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), the second enzyme of
the tyrosine catabolic pathway. Treatment with Nitisinon stops the flux through the tyrosine
catabolic pathway in order to prevent accumulation of toxic metabolites (MAA and FAA that are
seen as SA). In patients with tyrosinemia type 1 receiving NTBC the course of the disease improves
in terms of prognosis and avoidance of the sequelae.
Nitisinon is generally prescribed at 1.0 mg/kg/day, given in two divided doses. Dosage should be
adjusted to maintain blood Nitisinon levels between 40 and 60 μmol/L. Adverse effects of Nitisinon