Biochemical Relationships Between Reye’s and Reye’s-Like Metabolic and Toxicological Syndromes

Abstract

Reye's syndrome is a hepatic encephalopathy with fatty infiltration of the liver and is due to mitochondrial dysfunction. Knowledge of the mechanisms causing Reye's syndrome has been gained from the study of Reye's syndrome-like diseases, including inborn errors of mitochondrial energy production, viral disease and toxicological injury. Entry of fatty acids into mitochondria or beta-oxidation itself may be impaired. Toxins such as hypoglycin, pentanoate, valproate, salicylate, and their metabolites inhibit beta-oxidation pathways and can produce Reye's syndrome-like presentations. Biochemical manifestations of the diverse causes of Reye's syndrome-like disorders are similar and include: hypoglycaemia due to impaired gluconeogenesis, accumulation of fatty acids, fatty acyl CoAs, and acyl carnitines with depletion of free CoA and carnitine. Accumulated products may further injure mitochondria and exacerbate impaired beta-oxidation, uncouple oxidative phosphorylation or increase mitochondrial permeability. Mitochondrial swelling and steatosis of hepatic cells are the histological result. With the advances of biochemical techniques for the study of organic acid excretion patterns, serum fatty acid patterns and identification of enzymatic deficiencies in cells from patients with Reye's syndrome-like presentations, it is clear that Reye's syndrome is, in part, a collection of various inborn errors and toxicological states. Circumstances such as viral disease, prolonged fasting and drugs may precipitate clinical expression of these deficiencies as Reye's syndrome. As work progresses, further causes of Reye's syndrome will be identified.

Reye's and Reye's‐like syndromes

“…40 Moreover non-steroidal anti-inflammatory drugs such as sodium diclofenac and mephenamic acid can produce or aggravate Reye's syndrome. 41 Finally hypoglycin and pentanoate, plant toxins, present in some fruits, especially when unripe, 37 pesticides 34 and methyl bromide, used in industry, seem to be involved in severe Reye's-like syndromes. 42 …”

“…22 Moreover infective agent and/or pre-existent metabolic disorders (latent also) predispose to the chemically induced syndrome. 37 In particular, according to Glasgow and Middelton 38 some viruses can affect Kupffer cells with a consequent endotoxemic condition, accompanied by proinflammatory cytokines and especially of TNF-a release. 32 These phenomena downregulate gene expression of major cytochrome P-450 enzymes that are very important for metabolism of many endogenous and exogenous products, with a consequent damage of main mitochondrial functions.…”

“…37 In particular, primary or secondary b-oxidation defects, impaired gluconeogenesis and acyl CoA alterations affecting mitochondrial functions and its permeability, increase oxidative phenomena and interfere with detoxication processes, so predisposing to the outbreak of these syndromes. 37,[43][44][45] To this end Chang et al 46 also cite, especially in the case of Reye's-like syndrome urea cycle disorders, glycogen storage disease Ia (GSD Ia), primary carnitine deficiency, hereditary fructose intolerance, methylmalonic acidemia, 3-hydroxy-3-methylglutarate acidemia, and underline again the importance of fatty acid oxidative defects. Moreover, according to Heick et al 47 also ornithine carbamoyl transferase deficiency seems to predispose to Reye'slike syndrome.…”

Co‐ingestion of aspirin and acetaminophen promoting fulminant liver failure: A critical review of Reye syndrome in the current perspective at the dawn of the 21st century

“…1, [4][5][6]10,11 This situation has prompted warnings against using salicylates for children with infectious symptoms since the 1980s. 1,[4][5][6][7]10 The public well heeded these warnings, and in place of salicylates, acetaminophen was used for symptomatic control of paediatric viral illnesses.…”

“…Suggested natural substances that may have an association with Reye syndrome include hypoglycin, pentanoate, and plant toxins. [11][12][13] There are many natural products that are known to cause hepatic failure, which may …”