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The Mechanism for Aspirin or Salicylates Induced Reye's Syndrome in Children with Viral Infections


  • Reye's syndrome is a rare but serious condition that results in microvesicular hepatitic 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).
  • Approximately 3-5 days after the onset of the viral illness, the signs and symptoms of Reye's syndrome progress in the following order: persistent vomiting, unusual sleepiness, lethargy, disorientation and confusion, delirium, seizures and loss of consciousness.
  • The use of aspirin or salicylates is known to increase the risk for Reye's syndrome if used during a viral illness.
  • The underlying problem with the use of aspirin during a viral illness is an inhibition of fatty acid metabolism (oxidative phosphorylation and b-oxidation) in the liver.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: August 2015


  • Reye's 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 

    Given 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 exclusion.

    How does use of aspirin or salicylate increase the risk for developing Reye's syndrome? 
    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. 

    What effect does aspirin or salicylate have on fat accumulation and hepatocellular damage? 
    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  

    As 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 hepatocyte.14

    Unfortunately, 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.     

    How do these effects in the liver translate into the development of acute encephalopathy?
    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 death.1,2  

    Therefore, 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.


    1. National Reye's Syndrome Foundation.  What is Reye's Syndrome.  Last accessed on 02/04/2010.  
    2. National Institute of Neurological Disorders and Stroke.  National Institute of Health.  NINDS Reye's Syndrome Information Page.  Last accessed on 02/04/2010.  
    3. Reye RD, Morgan G, Baral J.  Encephalopathy and fatty degeneration of the viscera. A disease entity in childhood.  Lancet  1963;2:749-52.  
    4. Stechenberg BW, Keating JP, Koslov S et al.  Epidemiologic investigation of Reye syndrome.  J Pediatr  1975;87:234-7.  
    5. Belay 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.  
    6. Forsyth 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.  
    7. Borne 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.
    8. Glasgow JF and Middleton B.  Reye syndrome-insights on causation and prognosis.  Arch Dis Child 2001;85:351-3.  
    9. Meert KL, Kauffman RE, Deshmukh DR et al.  Impaired oxidative metabolism of salicylate in Reye's syndrome.  Dev Pharmacol Ther  1990;15:57-60. 
    10. Trost 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  1997;147:431-41.  
    11. Tomasova H, Nevoral J, Pachl J et al.  Aspirin esterase activity and Reye's syndrome.  Lancet  1984;2:43.  
    12. Glasgow 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  1999;1454:115-25.  
    13. Kroemer G. Zamzami N, Susin SA.  Mitochondrial control of apoptosis.  Immunol Today  1997;18:44-51.  
    14. 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. 
    15. Lieberman M. Marks AD.  Mark's Basic Medical Biochemistry A Clinical Approach. 3rd edition.  Wolters Kluwer/Lippincott Williams & Wilkins.  Philadelphia, PA.  2009.

MESH Terms & Keywords

  • Reye Syndrome, Viral Infections, Children and Aspirin Use, Aspirin Induced Reye Syndrome, Salicylic Acid Induced Reye Syndrome