Tyrosinaemia type I and NTBC (2‐(2‐nitro‐4‐trifluoromethylbenzoyl)‐1,3‐cyclohexanedione)

Abstract

In tyrosinaemia type I (McKusick 276700), fatal liver disease results either because of liver failure during infancy or early childhood or because of development of hepatocellular carcinoma during childhood or adolescence. This is caused by toxic metabolites which accumulate because of deficiency of fumarylacetoacetase, the last enzyme in the tyrosine catabolic pathway. NTBC is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase and has been shown to efficiently prevent tyrosine degradation, and production of succinylacetone, in patients with tyrosinaemia. Since the first trial of NTBC treatment for tyrosinaemia type I in 1991, over 220 patients have been treated by the drug using a protocol which includes regular follow-up with reports of clinical and laboratory investigations to the study centre in Gothenburg, where additional analysis of critical variables is done on regularly collected samples. The course of the disease in patients with acute tyrosinaemia has changed dramatically. Only 10% of the patients have not clinically responded to NTBC treatment. In half of these patients, successful liver transplantation has been performed which has further reduced the mortality rate during infancy to 5%. The international NTBC study has now been going for 5 years and data have emerged that indicate a decreased risk for early development of hepatocellular carcinoma in patients who started treatment at an early age. There are now 101 patients aged 2-8 years who have started NTBC treatment before 2 years of age, and no cancer has developed after 2 years of age among these patients. However, there is no safe age with respect to occurrence of liver cancer, which has been recognized at diagnosis at 1 year of age in one patient and after a few months of treatment in an infant who was given NTBC at 5 months of age.

Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice

“…This is in line with results from earlier smaller studies showing an increased risk for hepatocellular carcinoma when NTBC treatment was initiated at a later age [12],[15],[21]. Our results show that the risk for HCC is already increased when treatment is initiated beyond the newborn period.…”

Comparison of plasma and dry blood spots as samples for the determination of nitisinone (NTBC) by high-performance liquid chromatography–tandem mass spectrometry. Study of the stability of the samples at different temperatures

“…Recommended therapeutic concentration of NTBC is around 35 mol/L [16]. By this reason, most patients under treatment had rather similar plasma concentrations of the drug.…”

The HAG Mechanism: A Molecular Rationale For The Therapeutic Application Of Iron Chelators In Human Diseases Involving the 2-Oxoacid Utilizing Dioxygenases

“…These compounds act as chelators of the enzymes' non-heme iron and interfere with its catalytic function [11,13]. Aware that the metabolic block inherited in hepatorenal tyrosinemia causes the accumulation of hepatotoxins formed by human 4-hydroxyphenylpyruvate dioxygenase, Lindstedt, Holme, and Lock conceived the use of the acylcyclohexanedione NTBC to inhibit toxicant formation in affected children [87,88]. This herbicide use in humans has become the standard nontransplant treatment for tyrosinemia [89].…”