Hepatorenal tyrosinemia is a fascinating inborn error of metabolism that can affect numerous organs, particularly the liver, kidneys, and peripheral nerves. The first report of a patient with elevated blood tyrosine was by Medes in 1932 [1]. Patients with a more typical clinical and biochemical picture of tyrosinemia were then described in the late 1950s [2–5]. Since then, more than 500 patients have been reported in the literature [6–8] or enrolled in the International NTBC [2-(2-nitro-4-trifluoromethyl benzoyl)-1,3-cyclohexanedione] Trial. Previously, almost all patients died in infancy and early childhood, and only isolated case reports described affected adults. In the 50 years since the description of tyrosinemia [3], the course of the disease has been improved successively by the introduction of diet therapy, neonatal screening, and hepatic transplantation. The advent of liver and kidney transplantation as a definitive treatment [7–11] revolutionized the outcome. Recently, the availability of NTBC, a chemical now designated as nitisinone and commercialized as Orfadin (Swedish Orphan International AB), has provided hope for a nonsurgical solution for some patients. On a fundamental level, tyrosinemia raises questions in hepatology, biochemical and population genetics, cell biology, oncology, and public health.

PATHOPHYSIOLOGY

Tyrosinemia is caused by a deficiency of fumarylacetoacetate hydrolase (FAH; enzyme [EC] 3.7.1.2), the last enzyme of tyrosine degradation (Figure 29.1A). The site of the primary metabolic block in tyrosinemia was elegantly deduced by Lindblad et al. in 1977 [12] and subsequently confirmed enzymatically by several investigators [13–15].