What is the role of salicylates in the etiology of Reye syndrome?

Updated: Apr 02, 2018
  • Author: Debra L Weiner, MD, PhD; Chief Editor: Kirsten A Bechtel, MD  more...
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Answer

The association of Reye syndrome with salicylates, particularly aspirin, was demonstrated in several epidemiologic studies around the world. Less than 0.1% of children who took aspirin developed Reye syndrome, but more than 80% of patients diagnosed with Reye syndrome had taken aspirin in the past 3 weeks. A causal relation between Reye syndrome and salicylates has not been definitively established and has been questioned on the basis of biases and limitations in the studies, [1] but recommendations by government health agencies that children not be treated with salicylates led to an immediate and dramatic decrease in the incidence of Reye syndrome.

Results of in vitro studies are contradictory on impact of aspirin on beta-oxidation metabolism. One study demonstrated that salicylates decrease beta-oxidation of the long-chain fatty acid palmitate by cultured fibroblasts from children who recovered from Reye syndrome as compared with control subjects. [2] Another study showed that in two different cell lines, aspirin increased mitochondrial long-chain fatty acid oxidation, did not change oxidation of medium chain fatty acids, and inhibited peroxisomal fatty acid oxidation, which suggest that aspirin impairs long-chain fatty acid transport into mitochondria. [18] Some have postulated that salicylates stimulate the expression of inducible nitric oxide synthase (iNOS) because of the findings of iNOS stimulation in African children with fatal malaria, a disease that causes symptoms similar to those of Reye syndrome and is often treated with aspirin.

Recognition of the structural similarity between aspirin metabolites and enzyme substrates for the mitochondrial trifunctional enzyme important in beta-oxidation led to identification of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) component of the enzyme as the target of salicylate inhibition. [3] Absence of inhibition of beta-oxidation by salicylates in fibroblasts from patients with LCHAD deficiency substantiated the finding.


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