COMMENTHereditary tyrosinemia (HT) is a relatively uncommon disorder, although its manifestations offer a variety of fascinating paradigms concerning hepatic pathophysiology. The genetic defect in the disorder involves the enzyme, fumarylacetoacetate hydrolase (FAH), which converts fumarylacetoacetic acid to fumarate and acetoacetate in the last step of the phenylalanine-tyrosine pathway. Despite dietary control and recently described treatment with 2(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexane dione (NTBC), which interferes with upstream tyrosine catabolism and decreases production of deleterious metabolites, patients with HT may remain at risk for hepatocellular carcinoma (HCC). This causes quandaries in managing relatively asymptomatic patients, e.g., when should orthotopic liver transplantation (OLT) be considered, because OLT can cure HT and eliminate the risk for HCC. The oncogenetic mechanisms in HT are not fully understood; however, the metabolic consequences are complex, cellular perturbations may include the emergence of FAH-containing liver nodules, due to genetic reversion, or of resistant cell clones, and at some point, cell transformation might occur. 1 Several years ago, investigators produced novel mouse strains by targeted disruption of the 5 th exon of the FAH gene. 2 The resultant homozygous FAH ᭝exon5 mice exhibited neonatal lethality and other phenotypic similarities with the previously described lethal albino mouse, which also lacked the FAH gene. 3,4 The FAH ᭝exon5 mice can indeed be rescued with NTBC treatment, although this again does not necessarily prevent development of HCC. Based upon the reasoning that liver repopulation will ameliorate disease in the FAH ᭝exon5 mice, Overturf et al. began to document the fate of normal or genetically corrected transplanted hepatocytes in the liver. 5 Work by others showed that although transplanted hepatocytes integrated in the liver parenchyma, cells did not proliferate significantly in the normal liver. 6,7 In contrast, Overturf et al. found that normal hepatocytes underwent extensive proliferation in the liver of FAH ᭝exon5 mice that were not treated with NTBC. 5 An interesting finding was that genetically corrected mutant hepatocytes were also positively selected with restoration of the liver to normal. This was akin to extensive proliferation of normal transplanted hepatocytes in the liver of uPA transgenic mice, in which host hepatocytes are continuously depleted as well. 8 In additional studies, use of an adenoviral vector expressing the human FAH gene resulted in prolonged survival of thus treated FAH ᭝exon5 mice, with the liver now harboring hepatocytes with both normal, as well as undetectable, FAH content upon immunostaining. 9 However, a large proportion of the treated FAHD ᭝exon5 mice eventually developed HCC during long-term follow up, presumably because the fraction of genetically uncorrected hepatocytes remained under oncogenetic selection pressure. Nonetheless, these studies advanced insights into the potential and limitation...