Hepatorenal tyrosinemia

Douglas J Lanska MD FAAN MS MSPH (

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health, the Medical College of Wisconsin, and IM Sechenov First Moscow State Medical University has no relevant financial relationships to disclose.

Originally released June 1, 2013; last updated November 20, 2019; expires November 20, 2022

This article includes discussion of hepatorenal tyrosinemia, FAH deficiency, hereditary tyrosinemia type 1, fumarylacetoacetase deficiency, fumarylacetoacetate hydrolase deficiency, tyrosinaemia type 1, and tyrosinemia, type 1. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


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, 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.

A skeletal diagram of L-tyrosine Image: L-tyrosine (skeletal diagram)
A Three-dimensional model of L-tyrosine Image: L-tyrosine (3D model)
German chemist Justus von Liebig Image: German chemist Justus von Liebig
Tyrosine is a nonessential amino acid with a polar side group, 1 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 1 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 catecholamine derivatives of tyrosine include L-DOPA, dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine). Image: Tyrosine conversion to biologically important catecholamines

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 (Medes 1932). 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) (Kitagawa 2012).

The first typical patient with hepatorenal tyrosinemia was described in 1956 by Margaret D Baber at Edgware General Hospital in Middlesex, England (Baber 1956). Starting the following year, Kiyoshi Sakai and colleagues, at the Jikei University School of Medicine in Tokyo, published 3 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) (Sakai and Kitagawa 1957a; Sakai and Kitagawa 1957b; Sakai et al 1959; Kitagawa 2012).

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 (Zetterström 1963; Fritzell et al 1964; Halvorsen and Gjessing 1964; Gentz et al 1965; Gjessing and Halvorsen 1965; Taniguchi and Gjessing 1965). Shortly thereafter, a Canadian group also described the clinical and laboratory findings of hepatorenal tyrosinemia (Scriver et al 1966). Both the Scandinavian and Canadian groups suggested that the Japanese patients described earlier by Sakai and colleagues had the same disorder, ie, hepatorenal tyrosinemia (Kitagawa 2012).

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 (Lindblad et al 1977). This was subsequently confirmed with a direct enzyme assay.

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