Relationship between unusual hepatic acyl coenzyme A profiles and the pathogenesis of Reye syndrome

B. E. Corkey, D. E. Hale, M. C. Glennon, R. I. Kelley, P. M. Coates, L. Kilpatrick, C. A. Stanley

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Abstract

This study examines the relationship between impaired fatty acid oxidation and the pathogenesis of Reye syndrome. We present a hypothesis proposing that many clinical signs of this childhood disease are caused by accumulation of unusual acyl CoA esters, precursors to deacylated metabolites found in the patients' blood and urine. A new method was developed to measure acyl CoA compounds in small human liver biopsy samples, offering several advantages over previous techniques. A major finding was an accumulation in Reye syndrome patients of short- and medium-chain acyl CoA intermediates of fatty acids and branched-chain amino acid oxidation. These metabolites included octanoyl, isovaleryl, butyryl, isobutyryl, propionyl, and methylmalonyl CoA esters. The findings were explained in a model of hepatic fatty acid oxidation involving three interrelated pathways: mitochondrial β-oxidation, peroxisomal β-oxidation, and ω-oxidation in the endoplasmic reticulum. The results suggest that pathogenesis in Reye syndrome stems from generalized mitochondrial damage resulting in accumulation of acyl CoA esters. High levels of these compounds lead to inhibition of mitochondrial pathways for ureogenesis, gluconeogenesis, and fatty acid oxidation. The inhibited pathway, in turn, could cause the hyperammonemia, hypoglycemia, and hypoketonemia observed in patients. The model also explains underlying biochemical differences between patiens with Reye syndrome and medium-chain acyl CoA dehydrogenase deficiency, another disorder of fatty acid metabolism. Acetyl CoA levels, in the latter disease, were dramatically decreased, compared with both human controls and Reye syndrome patients.

Original languageEnglish (US)
Pages (from-to)782-788
Number of pages7
JournalJournal of Clinical Investigation
Volume82
Issue number3
DOIs
StatePublished - Jan 1 1988

ASJC Scopus subject areas

  • Medicine(all)

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    Corkey, B. E., Hale, D. E., Glennon, M. C., Kelley, R. I., Coates, P. M., Kilpatrick, L., & Stanley, C. A. (1988). Relationship between unusual hepatic acyl coenzyme A profiles and the pathogenesis of Reye syndrome. Journal of Clinical Investigation, 82(3), 782-788. https://doi.org/10.1172/JCI113679