Reye's syndrome

Author: matteo ripepi
Date: 13/01/2009


Matteo Ripepi, Francesca Solia


Reye's syndrome is primarily a children's disease, although it can occur at any age. It affects all organs but it is most harmful to the brain and the liver causing an acute increase of pressure in the brain (cerebral oedema) and a massive accumulation of fat in the liver, kidneys (fatty vacuolization) and other organs. RS is defined as a two-phase illness because it generally occurs in conjunction with a previous viral infection, such as influenza or varicella. The disorder commonly occurs during recovery from a viral infection, although it can also develop 3 to 5 days after the onset of the viral illness.
Many studies have demonstrated a strong association between aspirin taken for viral illnesses and the development of Reye’s syndrome (see epidemiology) and a generalized loss of mitochondrial function leading to disturbances in fatty acid and carnitine metabolism in the liver, brain, and muscle (see pathogenesis).


Reye’s syndrome occurs almost exclusively in children.
Many studies demonstrated a link between reye’s syndrome and aspirin or salycilates intake during the prodromes of a viral pathology.
The fatal rate is 36 percent. It's higher in children under 5 years old and in subjects with higher ammonia levels (45 microg/decilitre). link

American experience

In the US the association between aspirin intake and RS warned physicians from the beginning of 1980. Data collected from 1980 to 1997 had shown that RS cases decreased sharply after those warnings. After a peak of 555 cases in children (1980) the study found only 33 cases in 1987. More than 82 percent of affected had blood detectable salicylates.
During a period between 1991 to 1994 the true annual incidence of the desease found was 0.2-1,1 cases per million on a population of <18 years old.

British experience

In the UK in a period between 1982 and 1990 the warnings of the possible association of RS and salicylates started during 1986. Also in the islands was demonstrated a decline in RS after 1986. This decline involved the not use of salycilates in children and non only the improved diagnosis of Reye’s like syndrome, such as inheritated metabolic disorders.

French experience

In France the incidence of RS during 1996 and 1997 was similar to the US one and to the one of the countries where warning labels were already in use. There was a reduction in aspirin prescriptions too here due to warnings given by other European countries. This was sufficient to make the French drug agency adopting warning labels.



Lovejoy scale:


Reye’s syndrome can be suspected in children or in young subjects with previous
viral infection, especially of the respiratory tract, treated with salicylates presenting acute
encephalopathy, uncontrollable emesis associated with liver dysfunction.

The diagnostic criteria for Reye's syndrome are:

  • A clinical history of a biphasic illness with a preceding viral-like prodrome
  • A noninflammatory nature of the acute encephalopathy (fewer than 10 cells/mmm of cerebrospinal fluid)
  • Biochemical evidence of hepatocellular dysfunction (200 percent increase in serum transaminase and 150 percentincrease in blood ammonia level)
  • The exclusion of other causes of acute encephalopathy and hepatocellular dysfunction


Characteristic of Reye’s encephalopathy is the lack of inflammatory signs neither at meningeal nor perivascular level, but it is associated with elevation of intracranial pressure and cerebral oedema. Finally renal and cardiac failure can also be present.

Hepatomegaly and macroscopically fatty liver are found. Histology confirms the presence of a microvescicular fatty liver with no sign of inflammatory infiltration.


laboratory tests

Laboratory data show transaminase but not bilirubin increased levels, hyperammoniaemia, a prolonged prothrombin time, and especially in children of pre-school age marked hypoglycaemia. Moreover, different manifestations of metabolic disequilibria associated with acidosis are detected. Also, fluid pressure is generally increased with a normal proteinorrhachia and possible hypoglycorrhachia. However diagnostic criteria are unfortunately non-specific.


The cause of RS remains a mystery. However studies have shown (see epidemiology) that using aspirin or salicylate-containing medications to treat viral illnesses increases the risk of developing RS.

Drugs' role:

Recent studies have demonstrated that aspirin metabolites (salicylate, hydroxihippurate and gentisate) directly inhibit the long chain 3-hydroxyacil-Coa dehydrogenase activity and so the beta oxidation at this step

The mechanism of inhibition of beta-oxidation by aspirin metabolites in skin fibroblasts from Reye's syndrome patients and controls, 1999.

Another study has shown that toxins such as hypoglycin, pentanoate, valproate, salicylate, and their metabolites inhibit beta-oxidation pathways and can produce Reye's syndrome-like presentations

Biochemical relationships between Reye's and Reye's-like metabolic and toxicological syndromes, 1989.

Biochemical manifestations of the different 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.

Virus' role:

Influenza B virus has been aetiologically linked to Reye’s syndrome

Activated THP-1 cells depress mitochondrial respiration in Hep G2 cells infected with influenza B virus, 1994.

Studies on hepatic cells have demonstrated that the virus infects hepatic cells but not directly impairs beta oxidation. The infection acts in concert with soluble products of activated macrophages

Influenza virus-induced encephalopathy: clinicopathologic study of an autopsied case, 2000.

Reye’s syndrome encephalopathy results in vasogenic oedema with high levels of inflammatory cytokines, such as TNF-alpha and interluukin-6 as well as the cytocrome c apoptosis marker. A study demonstrates that human influenza virus can replicate in human vascular endothelial cells and induce apoptosis therein

Human influenza virus infection and apoptosis induction in human vascular endothelial cells, 2008.

Impaired beta-oxidation in mice changes the susceptibility to non-neurotropic influenza A virus which can so replicate in endothelial cells and cause brain oedema

Impaired long-chain fatty acid metabolism in mitochondria causes brain vascular invasion by a non-neurotropic epidemic influenza A virus in the newborn/suckling period: implications for influenza-associated encephalopathy, 2007.

Another hypothesis says that TNF-alpha induces apoptosis in astrocytes due to its effect on mitochondrial respiratory failure. This could cause a blood brain barrier damage found in influenza virus’ encephalitis

Hypothetical pathophysiology of acute encephalopathy and encephalitis related to influenza virus infection and hypothermia therapy, 2000.

Genetic deficiency's role and beta oxidation's role:

Table referred to article

The pathophysiological manifestations in patients with acyl-CoA dehydrogenation deficiencies resemble in many respect those seen in patients with Reye's syndrome, in which the fatty acid oxidation also seems to be compromised

Biochemical relationships between Reye's and Reye's-like metabolic and toxicological syndromes, 1989.

Ethiological factors have not been identified in Reye's syndrome, but in many patients blood accumulation of short- and medium-chain fatty acids has been found

The acyl-CoA dehydrogenation deficiencies. Recent advances in the enzymic characterization and understanding of the metabolic and pathophysiological disturbances in patients with acyl-CoA dehydrogenation deficiencies, 1985.

In multiple acyl-CoA dehydrogenase deficiency, Reye syndrome, and Jamaican vomiting sickness octanoyl-CoA accumulate . Octanoyl-CoA inhibits complex III of the respiratory chain. Impairment of mitochondrial energy metabolism by accumulating short- and medium-chain acyl-CoAs – especially octanoyl-CoA–act synergistically with other toxic metabolites inducing a secondary severe inhibition of key enzymes of mitochondrial energy metabolism resulting in multiorgan failure or even death if untreated

Impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on mitochondrial energy metabolism, 2008.

It was also found that ATP concentrations also were reduced with the higher octanoate concentration. These effects of octanoate may contribute to the severe astrocyte swelling observed in the brains of Reye's syndrome patients

Octanoic acid inhibits astrocyte volume control: implications for cerebral edema in Reye's syndrome, 1989.


The hypotheses before discussed poorly explain the pathogenesis of the brain swelling. It’s known that different viruses compete for iron with infected cells and induce an increase in ferritin synthesis (due to a rise in the production of cytokines such as IL-1, IL-6, TNF-alpha). A leak of iron so induced by the virus, that maybe can be also present before (conditions such as anaemia) can induce important metabolic effects:

low iron so:

  • An increase of NADH/NAD+ ratio

This can be translated in an increased production of fatty acid (due to high concentration level of Acetyl-Coa - Kerbs’ cycle is blocked-). This condition is similar to the alcoholic’s metabolism. Malonil-Coa, an intermediate of fatty-acid synthesis so accumulates and inhibits Carnitine-Acetil-Coa-acetyl-transferase (this is one of the most important feedbacks that regulate beta-oxidation). This is translated in a reduction in entering the mitochondria by fatty acid and this blocks beta-oxidation. An increase in NADH itself blocks beta oxidation acting on beta-hydroxyacyl-CoA-dehydrogenase. This can lead to the mitochondrial general loss of function, main feature of the syndrome. Fatty-acids can accumulate at the same time.

The consequence is an increase of VEGF. VEGF can be so implicated in the pathogenesis of cerebral oedema promoting angiogenesis and swelling.









anatomical (due its structure)

vascular (due to the local circulation)

physiopathological (due to tissue function and activity)


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