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Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3-cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH-/- mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.

The activity of the enzyme porphobilinogen synthase (EC 4.2.1.24) in erythrocytes from patients with hereditary tyrosinemia was less than 5% of that in a control group and the activity in liver tissue was less than 1% of the reported normal activity. Urine from patients with hereditary tyrosinemia contained an inhibitor that was isolated and identified as succinylacetone (4,6-dioxoheptanoic acid) by gas/liquid chromatography-mass spectrometry. Fresh urine samples contained succinylacetoacetate (3,5-dioxooctanedioic acid) as well as succinylacetone. The inhibition of porphobilinogen synthase explains the high excretion of 5-aminolevulinate observed in hereditary tyrosinemia. Succinylacetone and succinylacetoacetate presumably originate from maleylacetoacetate or fumarylacetoacetate, or both, and their accumulation indicates a block at the fumarylacetoacetase (EC 3.7.1.2) step in the degradation of tyrosine. We suggest that the severe liver and kidney damage in hereditary tyrosinemia may be due to the accumulation of these tyrosine metabolites and that the primary enzyme defect in hereditary tyrosinemia may be decreased activity of fumarylacetoacetase.In the inborn error of metabolism called hereditary tyrosinemia, the main clinical findings are liver failure, which develops into liver cirrhosis in early childhood, and multiple renal tubular defects with hypophosphatemic rickets (1, 2). The derangement in tyrosine metabolism (i.e., hypertyrosinemia and high urinary excretion of 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, and to a lesser extent 4-hydroxyphenylacetate) is due to a low activity of the enzyme 4-hydroxyphenylpyruvate dioxygenase [4-hydroxyphenylpyruvate:oxygen oxidoreductase (hydroxylating, decarboxylating), EC 1.13.11.27] (3), which catalyzes the formation of homogentisate (III) (Fig. 1) from 4-hydroxyphenylpyruvate (II).The increased excretion of these phenolic metabolites of tyrosine does not explain the liver and kidney damage in hereditary tyrosinemia because a similar large excretion has been found also in patients without liver and kidney disease-e.g., in a 5-year-old boy with multiple congenital anomalies and with negligible activity of soluble tyrosine aminotransferase (4) and in at least three other patients who were mentally retarded (2,5,6). A large excretion of the same metabolites has also been found in hereditary fructose intolerance (7).In 1967 we reported on a patient who had symptoms similar to those characteristic of acute intermittent porphyria (8). An increased excretion of 5-aminolevulinate has since then been observed in all patients studied by us, even in those without these symptoms (3, 9), but so far it has not been possible to find a biochemical link between the altered tyrosine metabolism and the increased excretion of a porphyrin precursor. In this report we present evidence for an enzyme defect in tyrosine catabolism in hereditary tyrosinemia that explains the increased excretion of 5-aminolevulinate. We also present a hypothesis

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In a double-blind, placebo-controlled trial, the effects of recombinant human growth hormone were studied on cerebrospinal fluid concentrations of growth hormone, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), monoamine metabolites, neuropeptides and endogenous opioid peptides. Twenty patients, 10 patients in each of 2 groups, with adult-onset, growth hormone deficiency were treated for 1 month with recombinant human growth hormone (0.25 U/kg/week) or placebo. All the patients received the appropriate thyroid, adrenal and gonadal hormone replacement. In cerebrospinal fluid, the mean concentration of growth hormone increased from 13.3 ± 4.4 to 149.3 ± 22.2 µU/1 (p = 0.002), during recombinant human growth hormone treatment. The cerebrospinal fluid IGF-1 concentration increased from 0.67 ± 0.04 to 0.99 ± 0.10 µg/1 (p = 0.005) and the IGFBP-3 concentration rose from 13.4 ± 1.25 to 17.5 ± 1.83 µg/l(p = 0.002). The dopamine metabolite homovanillic acid decreased from 282.1 ± 36.0 to 234.3 ± 26.5 nmol/l (p = 0.02) and the vasoactive intestinal peptide decreased from 4.1 ± 0.6 to 3.7 ± 0.4 pmol/l (p = 0.03). Cerebrospinal fluid immunoreactive β-endorphin increased from 24.4 ± 1.8 to 29.9 ± 2.1 pmol/l (p = 0.002). There were no significant changes compared to baseline in the cerebrospinal fluid concentrations of enkephalins, dynorphin A, the norepinephrine metabolite 3-methoxy-4-hydroxyphenyl-ethyleneglycol, the serotonin metabolite 5-hydroxyindoleacetic acid, γ-aminobutyric acid, somatostatin or corticotropin-releasing factor. We conclude that treatment with recombinat human growth hormone causes a tenfold increase in growth hormone in the cerebrospinal fluid, thereby indicating that recombinant human growth hormone passes the blood-cerebrospinal fluid barrier. The cerebrospinal fluid concentrations of IGF-1 and IGFBP-3 increased significantly. Simultaneously, the cerebrospinal fluid concentrations of homovanillic acid and vasoactive intestinal peptide decreased and the concentration of β-endorphin immunoreactivities increased significantly. These changes might explain the improved quality-of-life in patients with growth hormone deficiency following replacement therapy with growth hormone.

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In tyrosinaemia type I (McKusick 276700), fatal liver disease results either because of liver failure during infancy or early childhood or because of development of hepatocellular carcinoma during childhood or adolescence. This is caused by toxic metabolites which accumulate because of deficiency of fumarylacetoacetase, the last enzyme in the tyrosine catabolic pathway. NTBC is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase and has been shown to efficiently prevent tyrosine degradation, and production of succinylacetone, in patients with tyrosinaemia. Since the first trial of NTBC treatment for tyrosinaemia type I in 1991, over 220 patients have been treated by the drug using a protocol which includes regular follow-up with reports of clinical and laboratory investigations to the study centre in Gothenburg, where additional analysis of critical variables is done on regularly collected samples. The course of the disease in patients with acute tyrosinaemia has changed dramatically. Only 10% of the patients have not clinically responded to NTBC treatment. In half of these patients, successful liver transplantation has been performed which has further reduced the mortality rate during infancy to 5%. The international NTBC study has now been going for 5 years and data have emerged that indicate a decreased risk for early development of hepatocellular carcinoma in patients who started treatment at an early age. There are now 101 patients aged 2-8 years who have started NTBC treatment before 2 years of age, and no cancer has developed after 2 years of age among these patients. However, there is no safe age with respect to occurrence of liver cancer, which has been recognized at diagnosis at 1 year of age in one patient and after a few months of treatment in an infant who was given NTBC at 5 months of age.

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