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.
Patients are prone to infections at this stage accompanied by fever, vomiting, increased tendency to bleed, and diarrhea along with bloody feces as manifestations of sepsis. Other symptoms include enlarged liver, jaundice, and excess abdominal fluid.Sub-acute cases present between 6 months and the first year of life and the severity of liver disease is lessened to an extent. Again, synthetic function of the liver in terms of blood coagulation factors is impaired in addition to enlargement of the liver and spleen. The infant may also display a failure to thrive as their growth is limited by the disease. This growth impairment can manifest itself in rickets, which is the softening of bones.The final classification, chronic HT1, is detected with presentations occurring after one year of life. The course of the disease up to this point can lead to different ailments affecting the liver. Cirrhosis, liver failure, or cancer of the liver may present as a result of chronic liver disease. Additional symptoms common in this classification include cardiomyopathy, renal disease, and acute neurological crises. Liver
The liver is the organ affected most by Tyrosinemia Type I due to the high level of expression of the gene for fumarylacetoacetate hydrolase (FAH) in liver cells. The production of blood coagulation factors by the liver is disrupted, causing hemophiliac-like symptoms. Acute liver failure is common, especially in early life. Additionally, the synthesis of albumin in the liver may be defective, therefore leading to hypoalbuminemia. As the disease progresses, cirrhosis is common.