Lancet 1992 Oct 3;340(8823):813-7

Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase

Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B
Department of Clinical Chemistry, Gothenburg University, Sahlgren's Hospital,
Sweden.

Abstract
Liver transplantation is the only effective treatment for hereditary
tyrosinaemia type I (McKusick 276700). We have treated one acute and four
subacute-chronic cases with
2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), a potent
inhibitor of 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27), to prevent the
formation of maleylacetoacetate and fumarylacetoacetate and their saturated
derivatives. The oral daily dose was 0.1-0.6 mg/kg. The excretion of
succinylacetoacetate and succinylacetone decreased from 15-103 mmol/mol
creatinine to the detection limit or slightly above (ie, to 20-150 mumol/mol
creatinine). The concentration of succinylacetone in plasma decreased from
5.8-43 mumol/l to the detection limit (0.1 mumol/l) over 2-5 months of
treatment. The almost complete inhibition of porphobilinogen synthase in
erythrocytes was abolished and the excretion of 5-aminolevulinate decreased to
within or slightly above the reference range. The concentration of
alpha-fetoprotein decreased in four patients to 1.3-7.5% of initially high
values over 6-8 months. Improved liver function was reflected by normal
concentrations of prothrombin complex and in decreased activities of alkaline
phosphatase and gamma-glutamyltransferase in serum. Computed tomography revealed
regression of hepatic abnormalities in three patients. One patient developed
rickets 6 months before treatment and had excreted high concentrations of
markers of tubular dysfunction--after 3 weeks of treatment, this excretion had
disappeared. No side-effects were encountered. Inhibition of
4-hydroxyphenylpyruvate dioxygenase may prevent the development of liver
cirrhosis and abolish or diminish the risk of liver cancer. Normalisation of
porphyrin synthesis will eliminate the risk of porphyric crises. This type of
treatment may thus offer an alternative to liver transplantation in hereditary
tyrosinaemia