A pilot epidemiologic study of all cases of Reye and Reye-like syndromes was undertaken at 8 representative major hospitals in Peninsular Malaya from January 1st to December 31st 1986. The cases were classified as definitive Reye's syndrome, clinical Reye's syndrome and encephalo-hepatopathies. Less than 50% of cases reviewed fulfilled the National Center for Disease Control criteria for clinical Reye's syndrome. Causes of Reye-like syndromes/encephalo-hepatopathies included fulminant hepatitis, Japanese B encephalitis, dengue, septicaemia, and complex febrile fits. It was not possible to differentiate clinical Reye's syndrome from the other encephalo-hepatopathies by either the clinical features (except for jaundice) or biochemical parameters. Liver biopsy is necessary for a definitive diagnosis of Reye's syndrome in Malaysia, because of the high prevalence of Reye-like diseases. The mortality rate in the 2 groups of patients is similar. Ingestion of salicylates was not found to be significantly associated with Reye and Reye-like syndromes in this study.
The aetiology and pathogenesis of Reye's syndrome (RS) are incompletely understood. A number of environmental toxins and biological agents, including viruses, have been postulated to cause RS, either acting alone or synergistically. Most investigations have suggested that the primary insult is in the liver mitochondria, leading to a complex biochemical catastrophe, with death from encephalopathy. Margosa oil (MO), a long-chain fatty acid compound, has been shown to cause a Reye-like syndrome with death from hepatoencephalopathy, in children in Malaysia and India. The present time-course study performed in MO-administered mice showed the development of hepatic lesions with many features of RS. MO acts rapidly, within 30 min, on the nuclei of hepatocytes inducing mitoses and binucleated cells. This is followed by mitochondrial injury, with swelling, rarefaction of matrix, loss of dense bodies, pleomorphism, and loss of ribosomes starting at 60 min. There is loss of liver glycogen, and proliferation and hypertrophy of the endoplasmic reticulum (ER), followed by the presence of lipid droplets in the hyaloplasm, and globules within dilated cisterns of the ER. Additional fatty acids from lipolysis of body adipocytes, and fat globules from intestinal MO ingestion further aggravate the liver fatty change. There is evidence of fat globule ingestion by endocytosis into hepatocytes at the level of the sinusoids. The development of microvesicular liver steatosis and glycogen depletion due to involvement of liver cell organelles occur rapidly as in RS.
Glucose and steroids have been used in the treatment of children with Reye's syndrome, while carnitine and coenzyme Q10 have been the subject of some recent studies which suggest that these agents may have a role in the treatment of Reye's syndrome and Reye-like syndrome due to margosa oil poisoning. Because of the paucity of causes of Reye's syndrome seen at any one centre, the clinical variability of the disease, and limited knowledge of definite aetiologic factors, controlled clinical trials are not easy to carry out or to interpret in human cases. These caveats were overcome by evaluation of these four treatment modalities in an established margosa-oil-induced animal model of Reye's syndrome. Effectiveness of the treatment modalities was determined from clinical response and histopathologic parameters (grading of light microscopic fatty changes and ultrastructural changes in the hepatocytes). Results show that carnitine per se produces a small improvement in survival, but statistically, more significant benefit is seen with glucose administration. Carnitine plus 10% dextrose appears to produce better results. Evaluation of coenzyme Q10 and carnitine on histopathologic parameters in the liver after a sublethal dose of margosa oil showed no obvious ameliorating effect on liver pathology. Steroids (dexamethasone/methylprednisolone) had no beneficial effects in reducing mortality, affecting glycogen storage or lipid accumulation. Changes in the mitochondria, ribosomes and endoplasmic reticulum were unaltered from the groups treated with margosa oil alone. While glucose and carnitine supplements appear to be beneficial, the other modes of therapy do not seem to hold much promise in the treatment of Reye-like syndrome in the margosa-oil-induced animal model.
Dengue fever (DF) which is caused by four serotypes of dengue virus may in some cases progress into a life threatening situation of dengue haemorrhage fever (DHF) and dengue shock syndrome (DSS). It has been suggested that sequential infection with different dengue virus serotypes predisposes the patient towards DHF/DSS. We report here a primary dengue infection in a 10-year-old boy progressing from DF to DSS while under clinical observation. The report provides unequivocal evidence for the development of DSS in primary dengue infection caused by virus serotype 4. The close relationship between sequential changes in the levels of tumour necrosis factor (TNF), Interleukin 1 and 6 (IL-1 and IL-6) in the serum, to the clinical progression of the disease from DF to DHF/DSS and then to full recovery implicates a pathogenetic role for the inflammatory cytokines. The child also manifested clinical features consistent with Reye's syndrome and this suggests a common pathogenetic origin for DSS and the Reye-like syndrome induced by dengue virus.
Vomiting, drowsiness, metabolic acidosis, polymorphonuclear leucocytosis, and encephalopathy developed in thirteen infants within hours of ingestion of margosa oil. Liver biopsy of one infant and necropsy examination of ICR strain mice after experimentally induced margosa-oil poisoning demonstrated pronounced fatty infiltration of the liver and proximal renal tubules as well as cerebral oedema. Electron microscopy demonstrated mitochondrial damage. These findings indicate that margosa oil may be involved in the aetiology of Reye's syndrome among Indians in Malaysia.
Margosa oil (MO), a fatty acid-rich extract of the seeds of the neem tree and a reported cause of Reye's syndrome, has been used in the induction of an experimental model of Reye's syndrome in rats. It has been reported that MO causes a decrease in in vivo mitochondrial enzyme activity similar to that seen in Reye's syndrome. We have attempted to uncover some of the biochemical mechanisms of MO's toxicity by examining its effect in vitro on isolated rat liver mitochondria. Male rat liver mitochondria were isolated by centrifugation; oxygen uptake, reduced forms of cytochrome b, c + c1, a + a3, and flavoprotein, intramitochondrial concentrations of acetyl coA, acid-soluble coA, acid-insoluble coA, and ATP content were measured after incubation with and without MO. Our results reveal that MO is a mitochondrial uncoupler. State 4 respiration was increased while the respiratory control ratio was decreased. The intramitochondrial content of ATP was also decreased. There were substantial changes in the reduction of the respiratory chain components after incubation of mitochondria with MO. This decelerative effect on mitochondrial electron transport was alleviated by the addition of coenzyme Q and/or carnitine. These effects of MO on mitochondrial respiration may be due to changes in fatty acid metabolism caused by MO as MO caused a shift in the proportion of acid-soluble or acid-insoluble coA esters. Supplementary therapy with L-carnitine and coenzyme Q may be useful in the management of MO-induced Reye's syndrome.
An outbreak of food poisoning resulting in 13 deaths in children occurred in Malaysia during the Chinese Festival of the Nine-Emperor Gods in 1988. The offending food was a Chinese noodle called 'Loh See Fun' (LSF). The source was traced to a factory where a banned food preservative was added to make the LSF. The food poisoning was attributable to aflatoxins and boric acid. The clinical features included vomiting, pyrexia, diarrhoea, abdominal pain, anorexia, giddiness, seizures, and eventual coma. Initially, many presented with a Reye-like syndrome. Eleven post-mortem examinations were performed. The pathological findings included extensive coagulative necrosis of the liver with proliferative 'ductal/ductular metaplasia of the hepatocytes'. Giant cell formation, central vein sclerosis, bile stasis, and steatosis were also noted. There was presence of acute tubular necrosis, superficial upper gastrointestinal erosions, and ensuing encephalopathy. The eventual cause of death is acute hepatic and renal failure.