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  • Updated 05.14.2024
  • Released 06.01.2013
  • Expires For CME 05.14.2027

Hepatorenal tyrosinemia



In this article, the author explains the clinical and genetic background of hepatorenal tyrosinemia. Hepatorenal tyrosinemia is an inborn metabolic disease caused by a defective fumarylacetoacetate hydrolase enzyme, the last enzyme of the tyrosine degradation pathway. Untreated, hepatorenal tyrosinemia can lead to hepatocellular carcinoma.

Key points

• Hepatorenal tyrosinemia, or tyrosinemia type 1, is the most severe form of genetic tyrosinemia.

• Hepatorenal tyrosinemia is a devastating disorder of childhood that causes liver failure, painful porphyria-like neurologic crises, hypophosphatemic rickets, Fanconi syndrome, and hepatocellular carcinoma.

• If untreated, death typically occurs before 2 years of age, although some milder forms allow longer survival.

• Hepatorenal tyrosinemia is caused by defective fumarylacetoacetate hydrolase.

• The pathognomonic metabolite for hepatorenal tyrosinemia is succinylacetone.

• Secondary enzyme deficiencies in hepatorenal tyrosinemia (ie, delta-aminolevulinic acid dehydratase, methionine adenosyl transferase) result from inhibition by metabolites (ie, succinylacetone and fumarylacetoacetate), accumulating as a result of a primary deficiency of fumarylacetoacetate hydrolase. The secondary enzyme deficiency in delta-aminolevulinic acid dehydratase links tyrosinemia with porphyrin synthesis and is responsible for the porphyria-like crises in tyrosinemia.

• Hepatorenal tyrosinemia is treated by nitisinone administration and restriction of dietary tyrosine and phenylalanine. Occasionally, orthotopic hepatic transplantation may be indicated.

Historical note and terminology

Tyrosine (from the Greek tyros, meaning cheese), or 4-hydroxy-phenylalanine, was discovered in 1846 by German chemist Justus Freiherr von Liebig (1803-1873) in the protein casein from cheese.

Tyrosine is a nonessential amino acid with a polar side group, one of the 22 amino acids that are used by cells to synthesize proteins. Tyrosine phosphorylation, mediated by protein kinases (so-called receptor tyrosine kinases), is one of the key steps in signal transduction and regulation of enzymatic activity. Tyrosine is also a precursor to neurotransmitters (ie, catecholamines) and hormones (ie, thyroxine and melatonin), and, in particular, in dopaminergic cells in the brain, tyrosine is converted to L-DOPA by the enzyme tyrosine hydroxylase, and L-DOPA can in turn be converted to dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine).

Tyrosine conversion to biologically important catecholamines
Biologically important catecholamine derivatives of tyrosine include L-DOPA, dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine). Illustration by LHcheM (2012). (Courtesy of Wikimedia Commons. Creative Commons A...

In 1932, American biochemist Grace Medes (1886-1967), at the University of Minnesota Medical School in Minneapolis, first described “a new disorder of tyrosine metabolism” and called it “tyrosinosis” after observing 4-hydroxyphenylpyruvate in the urine of a 49-year-old man with myasthenia gravis (58). She proposed that the metabolic defect in this patient was a deficiency of 4-hydroxyphenylpyruvate dioxygenase, but the case remains puzzling and has since been assigned a separate OMIM number (76800) (48).

The first typical patient with hepatorenal tyrosinemia was described in 1956 by Margaret D Baber at Edgware General Hospital in Middlesex, England (06). Starting the following year, Kiyoshi Sakai and colleagues, at the Jikei University School of Medicine in Tokyo, published three reports describing the clinical, biochemical, and pathological findings of a 2-year-old boy with hepatorenal tyrosinemia who was then thought to have an “atypical” case of tyrosinosis (“atypical” because it differed from the supposedly prototypical case reported by Medes) (75; 76; 77; 48).

Then, between 1963 and 1965, Swedish pediatrician Rolf Zetterström (1920-2011) and associates at the Karolinska Institutet in Sweden published the first detailed descriptions of hepatorenal tyrosinemia and its variants, a disorder then hypothesized to be caused by a defective 4-hydroxyphenylpyruvate dioxygenase enzyme (102; 35; 45; 36; 39; 91). Shortly thereafter, a Canadian group also described the clinical and laboratory findings of hepatorenal tyrosinemia (83). Both the Scandinavian and Canadian groups suggested that the Japanese patients described earlier by Sakai and colleagues had the same disorder, ie, hepatorenal tyrosinemia (48).

From 1965, doubts arose over the hypothesis that hepatorenal tyrosinemia is caused by a defective 4-hydroxyphenylpyruvate dioxygenase enzyme, but it was not until 1977 that Bengt Lindblad and colleagues at the University of Gothenburg in Sweden showed that the primary enzyme defect in hepatorenal tyrosinemia involved the fumarylacetoacetate hydrolase enzyme (55). This was subsequently confirmed with a direct enzyme assay.

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