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.
Thus extreme caution with respect to iatrogenic risks is crucial to avoiding deaths or other adverse consequences in treatment, that of course prefigures a correct diagnosis. People with high exposure to Strongyloides stercoralis may mitigate the risk of strongyloidiasis hyperinfection associated with corticosteroid treatment, with the presumptive use of ivermectin. Such hyperinfection has been a particular concern during the COVID-19 pandemic because of the use of corticosteroids for treatment of COVID-19 symptoms. The CDC and other international bodies recommend the use of ivermectin for refugees from areas which have a risk of strongyloidiasis.During the 1940s, the treatment of choice was enteric coated tablets of 60 mg gentian violet, three times daily, for 16 days. The cure rate was reported to be only about 50 to 70 percent, requiring repeat courses. It is possible the cure rate was even less than that published in the literature, due to the difficulty in positively diagnosing infection. Epidemiology
Low estimates postulate it to affect 30–100 million people worldwide, mainly in tropical and subtropical countries, while higher estimates conservatively extrapolate that infection is upwards to or above 370 million people. It belongs to the group of neglected tropical diseases, and worldwide efforts are aimed at eradicating the infection. History
The disease was first recognized in 1876 by the French physician Louis Alexis Normand, working in the naval hospital in Toulon; he identified the adult worms, and sent them to Arthur Réné Jean Baptiste Bavay, chief inspector for health, who observed that these were the adult forms of the larvae found in the stool.