Toxic Actions of Salicylates on the Liver

Reye's syndrome is a hepathoencephalopathy that has been brought into connection with aspirin-

induced alterations in fatty acid metabolism, glu-coneogenesis, and urea metabolism in the liver (Section 3.3.3). Serum of patients with clinical Reye-like symptoms stimulated oxygen consumption in isolated liver mitochondria, indicating uncoupling of oxidative phosphorylation [209]. In addition, there was the generation of dicarboxylic acids that corresponded directly to the reduction in ATP formation by Reye patients' serum, demonstrating that they are central to the general disturbance of mitochondrial function [209]. These findings were taken as evidence by some authors for a causal relationship between salicylate (overdosing) and Reye's syndrome. There are, however, serious doubts in this hypothesis (Section 3.3.3). This chapter compares metabolic alterations in liver metabolism by salicylate intoxication with symptoms of Reye-associated hepatic failure.

Impaired b-Oxidation In both situations, the free fatty acid content in liver and plasma is markedly increased, in one study up to about 10-fold above normal [209]. However, similar to in vitro experiments with high-concentration salicylate exposure, the mitochondrial lesions in general were transient and fully reversible [226]. Morphologically, severe salicylate intoxication causes micro-vesicular steatosis of the liver that is also seen in Reye's syndrome. However, histopathology and ultrastructural pathology of liver biopsy specimens in Reye patients were different from those in salicylate intoxication [227, 228]. Acute highdose aspirin treatment in mice causes only mild microvesicular steatosis [199]. Moreover, micro-vesicular steatosis of the liver is not a unique etiologic entity and is seen in different forms of mitochondrial injury [229]. Inborn errors of ureagenesis may present with Reye-like micro-vesicular steatosis but with a morphology that is different from that observed in Reye's syndrome [230].

Medium-chain acyl coenzyme A dehydrogenase deficiency, an inherited defect of mitochondrial b-oxidation of fatty acids, was found to be associated with Reye-like symptoms [231] as was an inborn defect in the carnitine shuttle [232]. There is also fatty infiltration of the liver in these impairments of mitochondrial b-oxidation [198]. However, impaired b-oxidation of short or medium-chain fatty acids is not a typical feature of salicylate-induced liver toxicity [199]. Thus, salicylates will impair oxidative phosphorylation in the liver at high toxic concentrations [233, 234] (Section 3.2.3). These changes, however, are different from those obtained in patients with Reye's symptoms.

Dicarboxylic Acids A considerable percentage, at least 55% of total serum free fatty acids in Reye's syndrome, are dicarboxylic acids, the vast majority of them, 85-90%, being long chain [208-210]. Generation of these abnormal fatty acids is also seen at high salicylate levels. However, dicarboxylic acids are also found in inborn errors of metabolism in mitochondria or peroxisomes, such as Zellweger syndrome or neonatal adrenodystrophy [235]. In general, long-chain dicarboxylic acids may be formed as a secondary event in all forms of severely disturbed b-oxidation and are by no means Reye specific.

Plasma Salicylate Levels Exhaustion of the carnitine shuttle with subsequent generation and accumulation of dicarboxylic acid require high toxic concentrations of salicylate. In most reported cases of Reye's syndrome, serum salicylate levels, if measured at all, were not in the toxic range, and there are considerable doubts regarding the reliability of measurement of circulating salicylates in the clinical conditions of Reye-like diseaseby methods like the Trinder assay (Section 3.3.3).

Thus, there are not only some similarities between symptoms ofReye-like diseases and aspirin-related liver toxicity but also significant differences. In particular, there is definitely more than one reason for "Reye's syndrome" in the clinics - the diagnosis being one ofexclusion - and the finding that salicylates at selected experimental conditions may cause liver injury, specifically at high toxic in vitro concentrations maintained for many hours in largely protein-free media. This does not provide sufficient evidence or even causality between aspirin and Reye. Finally, there is no animal model for Reye's disease allowing studying the unique two-step process of this hepatic injury, initiated by certain virus infections.

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