syndrome is a rare but serious condition that results in microvesicular hepatic
steatosis (fatty changes of the liver) and acute encephalopathy (altered mental
status) primarily in children and teenagers recovering from a viral illness
(such as influenza or varicella zoster virus).1-4 While it is most common
in children, it can occur at any age.1,2 Approximately 3-5 days after the
onset of the viral illness, the signs and symptoms of Reye's syndrome present
in the following order: persistent vomiting, unusual sleepiness, lethargy,
disorientation and confusion, delirium, seizures and loss of
consciousness. Laboratory abnormalities common to Reye's syndrome include
a decrease in serum glucose and pH and increases in alanine aminotransferase
(ALT), aspartate aminotransferase (AST), and ammonia (NH3).1-3 Recovery
is dependent on the rapidity of syndrome progression, degree of swelling of the
brain, injury to the brain and timing of diagnosis.1,2
that viral illnesses in children and adolescents are common, why then is this
syndrome so rarely seen in clinical practice?
It appears to be more common in patients with an inherited metabolic disorder
such as enzyme defects of b-oxidation (required for fatty acid metabolism) or
the urea cycle.2,5 Furthermore, it has been associated with the use of
salicylates.3-6 Due to the rarity of this condition and atypical clinical
presentation, it is easily misdiagnosed and therefore is a diagnosis of
does use of aspirin or salicylate increase the risk for developing Reye's
In order to understand this effect, the syndrome needs to be
broken down into its individual components in the context of aspirin use and
then pull it all back together. These components include the process by
which aspirin contributes to fat accumulation in the liver and hepatocellular
damage that causes the microvesicular hepatic steatosis and the process that
result in acute encephalopathy. It is important to remember that this
syndrome occurs 3-5 days after the onset of the viral illness and follows a
specific and predictable progression. Thus, the effect on the central
nervous system (encephalopathy) is a direct result of the effects on the liver
(or hepatocytes). Lastly, the exact mechanism by which aspirin
contributes to the development of this syndrome has been a matter of debate for
a number of years, but recent advances in understanding the pathophysiology of
the syndrome have offered insight into the role of aspirin.
effect does aspirin or salicylate have on fat accumulation and hepatocellular
Aspirin is rapidly metabolized to salicylate by plasma cholinesterases.7
The high concentrations of salicylate is carried to the liver via the hepatic
portal vein where it undergoes hepatic uptake and first pass metabolism to form
a number of metabolites. The metabolites of interest in Reye's syndrome
include those that are formed by the hepatocyte mitochondria, which include
hydroxy hippurate (HHA) and gentisate.8,9 The hepatic uptake of
salicylate is important as the concentration in hepatocytes likely exceeds that
found in the serum or other tissues and salicylate is known to have a prolonged
biologic half-life during Reye's syndrome.10,11 The higher salicylate
concentrations within the hepatocyte, its slower rate of removal, and the
presence of a viral infection creates an environment that alters the metabolism
of fatty acids as well as the ability of the hepatocyte to protect itself from
damage and/or death.10,11
it relates to hepatic fat accumulation, salicylate and its metabolites (in
particular HHA and gentisate) have been shown to competitively inhibit the
enzyme long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) which is involved in
the b-oxidation of fatty acids.8,12 The inhibition of fatty acid
metabolism is important given the fact that hepatocytes utilize fatty acids via
oxidative phosphorylation through the tricarboxylic acid cycle (TCA) in the
mitochondria to make energy.8,13 Without the ATP generated through the
utilization of fatty acids, the hepatocytes (liver cells) can fail to maintain
their own intracellular environments/activities as well as the metabolism and
elimination of other metabolic by-products (such as conversion of ammonia
to blood urea nitrogen or BUN).14 This is especially true during a viral
infection where the metabolic demands are higher. The ATP deficient or
compromised hepatocytes are then at increased risk for initiating intracellular
cascades of injury and possible apoptosis (programmed cell death).14
These intracellular cascades are in part initiated by an increased
concentration of cytosolic (cytoplasmic) calcium, which is known to further
contribute to mitochondrial swelling, injury, and/or dysfunction.14
Damage to the mitochondria further impairs its ability to metabolize fatty
acids since mitochondrial damage can result in the loss of mitochondrial
membrane potential via the formation of a mitochondrial permeability transition
(MPT) pore and/or through the mitochondrial release of cytochrome c and other
pro-apoptotic proteins that initiate apoptosis (programmed cell death) of the
both of these effects on the mitochondria can be worsened or accelerated in the
presence of a viral infection and salicylate.1-6 In regard to
salicylates, their contribution to mitochondrial damage (beyond the inhibition
of fatty acid metabolism) is related to their ability to increase the onset for
a change in the MPT to be compromised.10 This not only accelerates the
hepatocellular damage by decreasing the liver's ability to handle the
accumulating fatty acids and metabolism of other metabolic by-products as
mentioned above (i.e., in particular, ammonia, NH3), but also disrupts normal
oxidative metabolism, thereby resulting in the accumulation pyruvate that is
shunted to form lactate.10,15 While the redirection of pyruvate to
lactate allows glycolysis to continue, the accumulation of lactate can decrease
the pH, thereby increasing the risk for metabolic acidosis.15
Therefore, the overall effects on the hepatocytes is an accumulation of
fat which causes the hepatic steatosis, cell injury or initiation of apoptosis,
and an inability to maintain other metabolic functions.
do these effects in the liver translate into the development of acute
The liver is the primary organ involved in the metabolism
and elimination of many end products of metabolism. In addition to using
free fatty acids for the generation of ATP, the normally functioning liver also
converts ammonia to a less toxic, more water soluble metabolite called blood
urea nitrogen (BUN).15 The accumulation of ammonia can result in
its entry into the central nervous system (CNS) resulting in nausea/vomiting
and altered mental status that is seen with the presentation of this
condition. The persistent vomiting classically seen with Reye's syndrome
can result in electrolyte abnormalities and dehydration, especially in young
children. This is complicated further by the liver's inability to help
regulate blood glucose levels and metabolize by-products of metabolism such as
lactate. In fact, patients may experience acid base imbalances and/or
experience hypoglycemia, which if low enough can also contribute to altered
mental status, seizures, and coma.1,2 As such, if Reye's syndrome is left
untreated, the outcome can range from minor brain damage to seizures and even
based on the clinical presentation, the histological changes seen in the liver
and brain as well as the changes in labs, it would appear that the underlying
problem is an inhibition of oxidative phosphorylation and b-oxidation (fatty
acid metabolism). Furthermore, if left untreated this syndrome can
progress to irreversible brain damage and/or death.
- National Reye's Syndrome Foundation. What is Reye's Syndrome. Last accessed on 02/04/2010.
Institute of Neurological Disorders and Stroke. National Institute of
Health. NINDS Reye's Syndrome Information Page. Last accessed on
RD, Morgan G, Baral J. Encephalopathy and fatty degeneration of the
viscera. A disease entity in childhood. Lancet 1963;2:749-52.
- Stechenberg BW, Keating JP, Koslov S et al. Epidemiologic investigation of Reye syndrome. J Pediatr 1975;87:234-7.
ED, Bresee JS, Holman RC et al. Reye's syndrome in the United States
from 1981 through 1997. N Engl J Med 1999;340:1377-82.
BW, Horwitz RI, Acampora D et al. New epidemiologic evidence
confirming that bias does not explain the aspirin/Reye's syndrome
association. JAMA 1989;261:2517-24.
R, Levi M, Wilson N. Nonsteroidal anti-inflammatory drugs. In Foye's
Principles of Medicinal Chemistry. Lemke TL, Williams DA, Roche VF, Zito
SW eds. 6th Ed. 2008:966-67.
- Glasgow JF and Middleton B. Reye syndrome-insights on causation and prognosis. Arch Dis Child 2001;85:351-3.
KL, Kauffman RE, Deshmukh DR et al. Impaired oxidative metabolism of
salicylate in Reye's syndrome. Dev Pharmacol Ther 1990;15:57-60.
LC, Lemasters JJ. Role of the mitochondrial permeability transition in
salicylate toxicity to cultured rat hepatocytes: implications for the
pathogenesis of Reye's syndrome. Toxicol Appl Pharmacol
- Tomasova H, Nevoral J, Pachl J et al. Aspirin esterase activity and Reye's syndrome. Lancet 1984;2:43.
JF, Middleton B, Moore R et al. The mechanism of inhibition of
beta-oxidation by aspirin metabolites in skin fibroblasts from Reye's
syndrome patients and controls. Biochim Biophys Acta
- Kroemer G. Zamzami N, Susin SA. Mitochondrial control of apoptosis. Immunol Today 1997;18:44-51.
- Kumar V, Abbas AK, Fausto N, Mitchell RN. Chapter 1. Cell injury, cell death, and adaptations. In: Robbins Basic Pathology. 8th edition. Saunders Elsevier. 2007:14-16.
- Lieberman M. Marks AD. Mark's Basic Medical Biochemistry A Clinical Approach. 3rd edition. Wolters Kluwer/Lippincott Williams & Wilkins. Philadelphia, PA. 2009.