Introduction

Hepatorenal tyrosinemia is a fascinating inborn error of metabolism that can affect numerous organs, particularly the liver, kidneys, and peripheral nerves. (For simplicity, this chapter uses the generic term tyrosinemia to refer to hepatorenal tyrosinemia (also known as fumarylacetoacetate hydrolase deficiency, tyrosinemia type I or congenital tyrosinosis; MIM 27670). Other forms of hypertyrosinemia are referred to by their specific names.) The first report of a patient with elevated blood tyrosine was in 1932 [1]. Patients with a more typical clinical and biochemical picture of tyrosinemia were then described in the late 1950s [2]. Since then, more than 500 patients have been reported in the literature or enrolled in the International NTBC Trial (of 2-(2-nitro-4-trifluoromethyl benzoyl)-1,3-cyclohexanedione (nitisinone)). 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, 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 revolutionized the outcome [3]. Recently, the availability of nitisinone, a chemical commercialized as Orfadin (Swedish Orphan International, Stockholm, Sweden), has provided hope for a non-surgical solution for some patients [4]. 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; EC 3.7.1.2), the last enzyme of tyrosine degradation (Figure 31.1a). The site of the primary metabolic block in tyrosinemia was elegantly deduced by Lindblad et al. in 1977 [5] and subsequently confirmed enzymatically by others [6]. The enzyme is a 419 amino acid residue cytosolic homodimer present in the liver and to some extent in the kidney, lymphocytes, erythrocytes, fibroblasts, and chorionic villi [7]. Human liver FAH cDNAs (GenBank NM000137) and the human gene FAH have been cloned and sequenced and the human gene mapped to chromosome 15q23-q25 [8]. Early studies of tyrosinemia showed that other enzymes of tyrosine degradation, particularly 4-hydroxyphenylpyruvate dioxygenase (4HPPD), are reduced in tyrosinemic liver. These changes have subsequently been shown to be secondary to the deficiency of FAH.