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A previously healthy 8-year-old Hispanic boy presented to the emergency department (ED) with a 2-day history of abdominal pain and 2 episodes of nonprojectile vomiting in the last 24 hours.
A previously healthy 8-year-old Hispanic boy presented to the emergency department (ED) with a 2-day history of abdominal pain and 2 episodes of nonprojectile vomiting in the last 24 hours. There were no other accompanying symptoms. Past medical history and review of symptoms was unremarkable. Initially, the child and mother denied any use of medications. The family history was noncontributory.
Physical examination revealed a well-developed, well-nourished obese child in no acute distress. Vital signs were normal. Head, eyes, ears, nose, and throat (HEENT) examination was normal, and lungs were clear with good air entry. Cardiovascular examination was normal. Abdominal examination showed no abdominal distention, bruises, or lacerations.
There was moderate tenderness in the epigastric area and right upper quadrant. Bowel sounds were normal. Rectal examination was normal, and stool guaiac was negative. Neurologic examination revealed normal sensorium. No obvious cranial nerve deficits and no motor and sensory deficits were noted. Deep tendon reflexes were symmetric, with downgoing toes bilaterally. Clinical suspicion of acute appendicitis, hepatitis, and acute cholecystitis prompted laboratory analysis and computed tomography (CT) scan of the abdomen.
Laboratory results revealed metabolic acidosis; elevated serum ammonia 270 mcg/dL (normal 15-45 mcg/dL); and marked elevation of liver enzymes, aspartate transaminase (AST) 1764 U/L (normal: 5-37 U/L), alanine transaminase (ALT) 2608 U/L (normal: 30-65 U/L), with a normal bilirubin level. The CT scan of the abdomen was deferred because preliminary laboratory tests suggested acute hepatic necrosis. Detailed inquiry regarding medication use suggested aspirin ingestion (2 tablets, strength unknown) 3 days prior to the patient presenting to the ED. Intravenous fluids were started; urine was sent for drug toxicology; and blood samples were drawn to determine prothrombin time and partial thromboplastin time.
While waiting for the laboratory results, the child became more combative and disoriented. This change in mental status prompted a diagnosis of hepatic encephalopathy, or Reye syndrome (Table).1 Appropriate management was begun. The patient was started on dextrose 10% in half normal saline solution, given at two-thirds maintenance. An urgent neurologic consultation was obtained. On initial neurologic evaluation, the child appeared somewhat sleepy but was arousable to verbal commands. The cranial nerve examination was normal with no papilledema. Motor examination showed no focal deficits. An urgent noncontrast head CT scan was normal, with no evidence of intracranial edema. Because of concerns about the potential increases in the intracranial pressure and cerebral herniation leading to mortality associated with Reye syndrome, the patient was transferred to a neurosurgical pediatric intensive care unit.
After transfer, the patient’s mental status continued to deteriorate and the child became comatose. A repeat CT scan of the head again revealed no evidence of increased intracranial pressure. An electroencephalogram (EEG) showed severe bilateral hemispheric slowing (2-3 Hz delta activity) with triphasic wave discharges. The clinical presentation and abnormal EEG findings were consistent with a diagnosis of hepatic encephalopathy.
The incidence of Reye syndrome has significantly decreased over the last decade. Reye syndrome most commonly manifests between the ages of 4 and 12 years in children residing in rural and suburban communities.2 This patient, however, was an 8-year-old boy from an inner-city neighborhood. Children aged younger than 5 years have a significantly higher case fatality rate than children aged older than 5 years. From December 1980 to November 1997, 1207 cases were reported to the Centers for Disease Control and Prevention, with a peak of 555 cases in 1980. From 1987 through 1993, 36 cases were reported each year, and from 1994 through 1997 no more than 2 cases were reported each year.3 This declining incidence is attributed to increased awareness of the association of Reye syndrome with the use of aspirin and other aspirin-containing medications in children with flu-like illnesses (ie, varicella).4
No statistical survey has been available since 1997. The majority of the cases have been reported in Caucasians (92.6%), as compared with other races.3 The patient, however, was a Hispanic child. Most cases occur in the months of December through April.
As mentioned previously, Reye syndrome is usually associated with viral infections, especially influenza B and varicella, when these are treated with salicylates. The case fatality rate is also increased by the presence of diarrhea during the antecedent illness.
Pathophysiology in Reye syndrome involves severe, generalized suppression of mitochondrial function, resulting in disturbances in fatty acid metabolism and carnitine function. The reasons for mitochondrial dysfunction are unknown.2 The activity of hepatic enzymes including ornithine transcarbamylase (OTC), carbamoyl phosphate synthetase (CPS), and pyruvate dehydrogenase are severely reduced. Hyperammonemia occurs because of acquired deficiency in the activity of OTC and CPS. The major pathologic lesion is microvesicular fatty accumulation in the liver. Electron microscopy shows characteristic changes in mitochondrial morphology. Similar pathologic changes are seen in the brain, with marked edema.
Reye syndrome exhibits a stereotypical biphasic course and usually occurs in a previously healthy child. Again, there is an etiologic link between Reye syndrome and the use of aspirin and viral infections. An upper respiratory tract infection or chicken pox is followed by an interval in which the child has seemingly recovered. Then, sudden onset of vomiting starts within 5 to 7 days of the viral illness. Delirium, followed by combative behavior, rapidly progresses to seizures, coma, and death.
Usually there are associated abnormalities of liver function with slight-to-moderate liver enlargement. Jaundice is not present at onset. Focal neurologic signs are usually absent. Cerebrospinal fluid pressure, however, is elevated. Although this case patient presented with mild abdominal complaints, he was found to have right-upper-quadrant abdominal tenderness on clinical evaluation. Assessment of liver function revealed marked elevation of liver enzymes, prompting the diagnosis of Reye syndrome. A review of the literature shows that abdominal pain, as seen in this case, is an uncommon presenting symptom of Reye syndrome. In atypical cases such as this patient, early diagnosis can be aided by a high level of clinical suspicion and assessment of liver function.
Disease progression is usually graded according to severity. Grades 1 through 3 represent mild-to-moderate illness. Grades 4 and 5 represent severe illness. The activity of mitochondrial enzyme glutamate dehydrogenase is greatly increased, and there is 3-fold or higher elevation in serum ammonia levels. Some patients have hypoprothrombinemia, which is refractory to vitamin K therapy. Hypoglycemia is characteristically seen in younger patients, although this patient did not have hypoglycemia.
In recent years, several inherited mitochondrial hepatopathies have been identified that produce an illness similar to Reye syndrome.5 In children younger than age 5 years, other metabolic diseases such as organic aciduria and defects in fatty acid oxidation metabolism like acyl-CoA dehydrogenase deficiency need to be investigated.
Management of Reye syndrome varies with severity of illness. All cases are hospitalized for observation and management. Aggressive therapies are needed in patients with rapid progression and neurologic deterioration. All patients should receive 10% to 15% glucose initially. In patients with cerebral edema, fluids should be restricted to two-thirds maintenance. In more severely ill patients, aggressive management of raised intracranial pressure is needed with intracranial pressure monitoring.
Despite aggressive management, the patient’s liver function deteriorated and his neurologic status worsened. He was electively intubated and transferred to a pediatric liver transplant center.
1. Weiner DL. Reye syndrome differential diagnoses. Medscape. Available at: http://emedicine.medscape.com/article/803683-differential. Updated April 2, 2015. Accessed December 8, 2015.
2. Balistreri WF. Reye syndrome and “Reye-like” diseases. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, PA: W.B. Saunders; 2000:1215-1216.
3. Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye’s syndrome in the United States from 1981 through 1997. N Engl J Med. 1999;340(18):1377-1382.
4. Hurwitz ES, Barrett MJ, Bregman D, et al. Public Health Service study of Reye’s syndrome and medications. Report of the main study. JAMA. 1987;257(14):1905-1911.
5. Greene CL, Blitzer MG, Shapira E. Inborn errors of metabolism and Reye syndrome: differential diagnosis. J Pediatr. 1988;113(1 pt 1):156-159.
Dr Nibhanipudi is professor of clinical emergency medicine, New York Medical College, Valhalla, New York. Dr Habal is assistant clinical professor of emergency medicine, New York Medical College. Dr Jain is attending physician-NICU at Kings County Hospital Center, Brooklyn, New York. The authors have nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.