Late Development of Hepatocellular Carcinoma in Tyrosinemia Type 1 Despite Nitisinone (NTBC) Treatment

Hepatocellular carcinoma requiring liver transplantation in hereditary tyrosinemia type 1 despite nitisinone therapy and α1‐fetoprotein normalization

“…Van Ginkel et al reported a child with HT1 who developed HCC without an increase in AFP levels and changes on imaging, although her AFP never normalized while on NTBC 6 . Similarly, Almuqbil et al reported a child with HT1 with delayed diagnosis and initiation of NTBC treatment who had an acute elevation of AFP and developed HCC 10 …”

“…8 In addition to delayed NTBC treatment, other predictors of HCC development include persistently abnormal or slow decline of AFP, and patients who were already cirrhotic at diagnosis. 5,6,9 Previous reports of HCC in HT1 patients have been in those whose AFP never normalized on NTBC treatment, 4,[10][11][12] or in those who did not receive NTBC therapy. [13][14][15] The risk of HCC remains unclear in those who normalize AFP after starting NTBC therapy.…”

In vivolentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions

“…Remarkably, animals treated adequately with NTBC showed increases in these liver injury and tumor-associated genes, which may explain the robust data now available in humans demonstrating development of cirrhosis and HCC in HT1 patients despite optimal and compliant NTBC therapy. 7–10, 71, 72 In addition, like wild-type animals, pigs treated with LV-FAH have normal, undetectable levels of AFP at one year, which is in stark contrast to undertreated NTBC FAH-deficient animals. This further supports our proposal of LV-FAH as an acceptable advancement in the treatment of HT1 in lieu of chronic NTBC maintenance therapy, which does not prevent development of inflammation, fibrosis, and HCC due to residual progression of tyrosine metabolism through the degradation pathway resulting in production of toxic metabolites.…”

“…6 A number of case reports and series point to the development of fibrosis, cirrhosis, and HCC despite NTBC therapy, especially with later initiations of therapy. [7][8][9][10] The frequency of HCC within the limited follow-up period available for patients treated with NTBC appears to be <1% if started prior to 1 year of age, 7% if started between 1 and 2 years of age, 21% if started between 2 and 7 years of age, and 35% if started after 7 years of age. 11 Therefore, these patients require lifelong HCC surveillance with alphafetoprotein (AFP) levels drawn every 3 to 6 months.…”

In vivo quantitative photoacoustic evaluation of the liver and kidney pathology in tyrosinemia

“…The FAH enzyme mainly in the liver and kidney catalyzes the last step of tyrosine metabolism [2] , [3] . Metabolic block of the step of FAH induces accumulation of toxic metabolites and further results in severe liver damage, nodular liver cirrhosis, renal tubular defects, and risk of hepatocellular carcinoma [4] , [5] , [6] . Survivors of these devastating complications often transitioned to hepatocellular carcinoma with lifetime frequencies as high as 37 % [7] , [8] .…”