Nitisinone inhibits the conversion of 4-OH phenylpyruvate to homogentisic acid by 4-Hydroxyphenylpyruvate dioxygenase, the second step in tyrosine degradation. By inhibiting this enzyme, the accumulation of the fumarylacetoacetate is prevented. Previously, liver transplantation was the primary treatment option and is still used in patients in whom nitisinone fails.Clinical treatment of HT1 relies on medications and strict regulation of diet. Nitisinone and dietary restrictions that decrease the amount of tyrosine and phenylalaine absorbed from the GI tract during protein digestion are used in combination as therapeutic measures that control the disease state if they are continued indefinitely. If not, there is a lack of control over the disease, resulting in continued liver and kidney damage, contributing to organ failure and death. In this case, a liver transplant may be required. Levels of SA are monitored throughout treatment in order to assess treatment effectiveness. Diet
The prescribed diet for treatment of HT1 is low in protein. Patients received amino acid supplements lacking tyrosine and phenylalanine in order to acquire sufficient protein. It is recommended that tyrosine levels remain below 500 μmol/L. Phenylalnine is the precursor to tyrosine. The ideology behind maintaining low tyrosine levels is two-fold. Firstly, it prevents the toxic metabolic intermediates from accumulating as a result of the dysfunctional tyrosine metabolic pathway. Prior to the introduction of nitisinone, this was the main treatment measure. Secondly, the mechanism of action of nitisinone is prevention of any tyrosine metabolism, thus it is important to prevent tyrosine from accumulating.
Fumarylacetoacetate accumulates in hepatocytes and proximal renal tubal cells and causes oxidative damage and DNA damage leading to cell death and dysfunctional gene expression which alters metabolic processes like protein synthesis and gluconeogenesis. The increase in fumarylacetoacetate inhibits previous steps in tyrosine degradation leading to an accumulation of tyrosine in the body. Tyrosine is not directly toxic to the liver or kidneys but causes dermatologic and neurodevelopmental problems. Tyrosine metabolic pathway
Fumarylacetoacetate hydrolase (FAH) is the final enzyme in the tyrosine metabolic pathway. The mutation of FAH enzyme results in nonfunctional FAH in all cells expressing this gene and thus metabolizing tyrosine is impaired. FAH catalyzes the conversion of fumarylacetoacetate to fumarate and acetoacetate. Loss of FAH results in the accumulation of upstream compounds in the catabolic pathway. These include maleylacetoacetate (MAA) and fumarylacetoacetate (FAA). MAA and FAA are converted to succinylacetoacetate (SAA) which is then catabolized to succinylacetone (SA).The accumulation of MAA, FAA, and SA in cells inhibits the breakdown of thiol derivatives, leading to post-translational modifications to the antioxidant glutathione. This inhibits the antioxidant activity of glutathione, leading to reactive oxygen species (ROS) damaging cell components. Over time, the combined effect of accumulation of toxic metabolic intermediates and elevated ROS levels in liver and kidney cells leads to apoptosis in these tissues which ultimately results in organ failure. Accumulated SA in liver and kidney cells results in its release into the bloodstream, which leads to secondary effects. SA inhibits the enzyme 5-ALA dehydratase which converts aminolevulinic acid (5-ALA) into porphobilinogen, a precursor to porphyrin.