Pharmacogenetic Analysis of an 8-Year Old Girl with Reye Syndrome Associated with Use of Naproxen.

BACKGROUND Reye syndrome is a rare, yet potentially life-threatening disease characterized by acute encephalopathy and hepatic failure. This report presents the case of an 8-year-old girl with Reye syndrome and seizures after the use of naproxen. CASE REPORT An 8-year-old girl experienced a 3-day episode of fever and abdominal pain. After receiving naproxen (375 mg twice daily) starting from day -3, she exhibited hypotension, tonic seizure, and loss of consciousness (day 1). Physical examination and laboratory test results revealed acute kidney injury, metabolic acidosis, and elevated levels of lactate dehydrogenase (LDH), liver enzymes, and ferritin. On day 2, the maximum values of aspartate aminotransferase, alanine aminotransferase, LDH, creatinine, and ferritin were 955 U/L, 132 U/L, 8040 U/L, 2 mg/dL, and >40000 ug/L, respectively. She was given supportive care and recovered after 11 days (day 12), with normalization of kidney function and metabolic abnormalities. To identify possible genetic polymorphisms associated with the patient's symptoms, genotypes were tested using a drug metabolizing enzymes and transporters (DMET) gene chip. Among genes involved in the metabolism of naproxen, UGT1A6 (*1/*2) and UGT2B7 (*1/*2) resulted in possibly decreased function. Other results which may have had clinical significance included homozygote results for NAT2*6/*6 (rs1799930). CONCLUSIONS A rare case of Reye syndrome after administration of naproxen was presented in this case. A DMET gene chip was used to screen for possible genetic polymorphisms associated with Reye syndrome, but the result was inconclusive.

Atypical Reye syndrome: three cases of a problem that pediatricians should consider and remember.

INTRODUCTION: Reye syndrome is a rare acquired metabolic disorder appearing almost always during childhood. Its aetiopathogenesis, although controversial, is partially understood. The classical disease is typically anticipated by a viral infection with 3-5 days of well-being before the onset of symptoms, while the biochemical explanation of the clinical picture is a mitochondrial metabolism disorder, which leads to a metabolic failure of different tissues, especially the liver. Hypothetically, an atypical response to the preceding viral infection may cause the syndrome and host genetic factors and different exogenous agents, such as toxic substances and drugs, may play a critical role in this process. Reye syndrome occurs with vomiting, liver dysfunction and acute encephalopathy, characterized by lack of inflammatory signs, but associated with increase of intracranial pressure and brain swelling. Moreover, renal and cardiac dysfunction can occur. Metabolic acidosis is always  detected, but diagnostic criteria are not specific. Therapeutic strategies are predominantly symptomatic, in order to manage the clinical and metabolic dysfunctions. CASE REPORTS: We describe three cases of children affected by Reye syndrome with some atypical features, characterized by no intake of potentially trigger substances, transient hematological changes and dissociation between hepatic metabolic impairment, severe electroencephalographic slowdown and slightly altered neurological examination. CONCLUSIONS: The syndrome prognosis is related to the stage of the syndrome and the rapidity and the adequateness of intensive care treatments. The analysis of the patients leads to a greater awareness of the difficult diagnosis of this not well completely known syndrome.

Co-ingestion of aspirin and acetaminophen promoting fulminant liver failure: A critical review of Reye syndrome in the current perspective at the dawn of the 21st century.

In the paediatric population, there is some evidence of possible interaction, synergism, and co-toxicity of aspirin and acetaminophen. The toxicity of salicylates such as aspirin in this population is well known and documented, specifically in the form of Reye syndrome. The possible toxic synergism with aspirin and acetaminophen, however, is not previously described; though case reports suggest such co-toxicities with low levels of aspirin and other compounds can exist. In vitro studies into mechanistic processes of salicylate toxicity propose that there is a bi-directional link and potentiation with glutathione (GSH) depletion and salicylate toxicity. Data may suggest a plausible explanation for salicylate and acetaminophen toxic synergism. Further studies investigating this potential toxic synergism are warranted. Given the lack of awareness in the clinical community about potential toxic synergism between these relatively common medications, caution is advised in the co-administration of these drugs, particularly in communities using natural or alternative therapy.

REYE (RAY'S) SYNDROME: A PROBLEM EVERYONE SHOULD REMEMBER.

Reye syndrome is a rare but a very dangerous emergency that children and teenagers suffer. This threatening condition occurs during the treatment of fever in the clinical course of viral diseases with drugs containing acetylsalicylic acid and other salicylates. The high mortality rate from this disease is associated with the development of a rapidly progressing toxic encephalopathy and hepatic insufficiency. The etiology and pathogenesis of the Reye syndrome, despite the large number of investigations, is not clear enough. Today, special attention is paid to the development of so-called Reye-like syndromes in the context of congenital metabolic defects, although cases of the true Reye syndrome occur quite often. In spite of the long discussion among scientists, the effect of acetylsalicylic acid is an important factor of development of this pathological syndrome. Taking this fact into consideration, the use of acetylsalicylic acid by children, especially in case of colds, should be strictly controlled by a doctor and parents should be informed about possible complications, especially the development of the Reye syndrome. This issue is very urgent in countries with non-prescription antipyretics realization and a high percentage of self-treatment among patients.

[ACTION OF L-CARNITINE, CORVITIN AND THEIR COMBINATION ON FUNCTIONAL STATE OF LIVER IN EXPERIMENTAL MODEL OF REYE SYNDROME IN RATS].

Administration of Aacetylsalicylic acid in children with viral infections (influence B, chickenpox) can be related with development of Reye syndrome - severe encephalopathy and liver insufficiency with mortality in 50% of cases. During Reye syndrome most important is deficiency of carnitine and hepatocyte damage. Decreased amount of carnitine impairs the energy function of mitochondria and gluconeogenesis as well as production of urea. As a result develops toxic encephalopathy and liver insufficiency. The goal of the research was assessment of efficacy of L-Carnitine, Corvitin and their combination on functional state of liver in experimental model of Reye Syndrome in rats. The study was performed on mature white male Wistar rates with body mass 150-180g. 50 rats were randomly divided into 5 groups (10 rats in each group). The model of Reye syndrome was induced in accordance with A.Vengersky's method. Intraperitoneal administration of 4-pentenoic acid was performed once daily during seven days, the used dosage was 20mg/kg. The treatment of toxic hepatitis was carried with intraperitoneal administration of L-Carnitine 300mg/kg, Corvitine 100mg/kg and concurrent administration of these drugs. Monotherapy with Corvitin and L-Carnitin successfully improved liver function and equally decreased indicators of hepatocyte's cytolyses and increased levels of glucose and urea. The markers of cholestasis was slightly more improved during use of L-Carnitine. Simultaneous use of both drugs was effective in rats with Reye syndrome, indicators of liver damage normalized and herewith, no mortality outcome was observed. The most pronounced hepatoprotective effect of concurrent administration of L-Carnitine and Corvitin may be due to synergic action of these drugs and such regime can be recommended for correction of liver function during Reye syndrome.

Resveratrol protects against experimental induced Reye's syndrome by prohibition of oxidative stress and restoration of complex I activity.

This study was designed to investigate whether resveratrol could provide protection against Reye's syndrome induced by 4-pentenoic acid in Wistar albino rats. Compared with rats with untreated Reye's syndrome, 1 h pretreatment by low dose resveratrol (10 mg/kg by oral gavage) resulted in marked amelioration in liver functions in the form of significant decrease in serum transaminases (AST, ALT) and plasma ammonia levels, shortening of prothrombin time, and increase in serum albumin levels. In addition, resveratrol prohibited oxidative stress markers, as indicated by a significant increase in GSH and decrease in MDA, with restoration of complex I activity in liver tissues. The classical histopathological presentation in Reye's syndrome of microvesicular steatosis by light microscope and mitochondria distortion by electron microscope has been improved by resveratrol pretreatment. The efficient protection by resveratrol was determined by normalization in serum levels of AST and albumin, as well as complex I activity, GSH, and MDA. In conclusion, pretreatment by resveratrol in low doses could protect against Reye's syndrome partially via prohibition of oxidative stress and restoration of complex I activity. This may provide the opportunity to reconsider aspirin therapy for infants and young children. However, the verification of such results in clinical practice remains a challenge.

[21-year-old woman with Reye's syndrome after influenza]. / 21-jährige Patientin mit Reye-Syndrom nach grippalem Infekt.

HISTORY AND ADMISSION FINDINGS: A 21-year old woman was referred to the hospital because of progressively deteriorating consciousness. Initially agitation and irritability, later confusion and delirium predominated. Previously influenza with high temperature, headache and vomiting had occurred and been treated with acetylsalicylic acid for some days. Non preliminary diseases were reported. CLINICAL INVESTIGATION: Besides of the deterioration in consciousness no clinical or neurological abnormalities were found. Electroencephalography demonstrated general abnormalities of medium range. Cranial magnetic resonance imaging and liquor investigations showed no pathological findings. In laboratory tests a marked increase of transaminases and ammonia were found. The toxicological screening was normal. TREATMENT AND COURSE: A hepatic encephalopathy due to acute hepatic failure was diagnosed and a detoxication of ammonemia with lactulose was started immediately. Transjugular liver biopsy showed a marked fattening of liver tissue without serological or histological findings for a reason. Because of progressive deterioration in consciousness mechanical ventilation became necessary. Despite of a rapid decline of ammonium serum levels further neurological deterioration occurred. Cranial computed tomography showed oedema of the cerebrum with beginning cerebral occlusion. Despite immediate therapy of cerebral oedema the patient died because of secondary cerebral oedema in hepatic encephalopathy. CONCLUSION: Reye's syndrome is an acute illness characterized by hepatic encephalopathy and fatty degeneration of the liver. It often occurs after viral infections. After a viral infection that was eventually treated with acetylsalicylic acid Reye's syndrome has to be discussed after exclusion of common causes of hepatic failure.

Linking drugs to obscure illnesses: lessons from pure red cell aplasia, nephrogenic systemic fibrosis, and Reye's syndrome. a report from the Southern Network on Adverse Reactions (SONAR).

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

Antiplatelet therapy in children: why so different from adults'?

Antiplatelet agents are administered in the treatment of a large number of adult diseases: coronary heart disease, ischemic stroke, peripheral arterial disease, arrhythmias with their thromboembolic complications, primary and secondary prevention. In childhood however, the situation is substantially different. The lack of large interventional trials on the use of antiplatelet drugs in children, has led to greater uncertainty, and a less extensive use of these drugs, limited to fewer indications. The purpose of this article was to review the studies conducted to date on the use of antiplatelet agents in children. A concerted effort has been made to identify which are the shared therapeutic indications of this class of compounds, the recommended dose, the contraindications and the possible side effects. In brief, an attempt has been made to ascertain the interesting potential of these drugs which are so often neglected in children.

Fatal case of Reye's syndrome associated with H3N2 influenza virus infection and salicylate intake in a 12-year-old patient.

We describe a fatal case of Reye's syndrome in a 12-year-old male patient during an influenza A (H3N2) infection for which he received salicylates. In the current situation of the novel A/H1N1 virus pandemic, we believe that it is of high importance to emphasize the risks associated with salicylate intake to avoid the reappearance of Reye's syndrome.

Reye syndrome and liver transplantation.

Reye syndrome is a rare, but severe and often fatal disease. The etiology of the classical Reye syndrome is unknown, but it is typically preceded by a viral infection with a free interval of three to five days. The main physiopathological hypothesis is a mitochondrial metabolism insult causing acute liver failure and encephalopathy. Survivors present serious neurological sequelae. The treatment of Reye syndrome is usually medical with intensive care management. Herein, we present the clinical case of a six-month-old baby diagnosed with Reye syndrome with a fulminant hepatitis, who was successfully liver transplanted with an auxiliary partial orthotopic liver transplantation.

FPIN's Clinical Inquiries. Aspirin use in children for fever or viral syndromes.

Aspirin should not be used to treat acute febrile viral illness in children. (Strength of Recommendation [SOR]: C, based on case-control studies). Although no causal link has been proven, data from case-control and historic cohort studies demonstrate an association between aspirin use and Reye syndrome. The risk of Reye syndrome decreases with age, becoming extremely rare by the late teenage years. Other nonsteroidal anti-inflammatory drugs are effective antipyretics and are not associated with the constellation of symptoms seen in Reye syndrome, which includes nausea, vomiting, headache, excitability, delirium, combativeness, and coma. Aspirin use in children younger than 19 years should be limited to diseases in which aspirin has a proven benefit, such as Kawasaki disease and the juvenile arthritides. (SOR: C, based on expert opinion).

Reyes's syndrome, encephalopathy, hyperammonemia and acetyl salicylic acid ingestion in a city hospital of Buenos Aires, Argentina.

Twelve cases of Reye's syndrome are presented with different degrees of encephalopathy, hyperammonemia and hypoglycemia; associated to acetyl salicylic acid (ASA) ingestion. The aim of the present retrospective study was to describe our experience in selected patients with Reye's syndrome associated to the ASA ingestion and to underline the influence of hyperammonemia on Reye's encephalopathy. All the cases presented moderate hyperbilirubinemia, elevated alanine aminotransferase, aspartate aminotransferase with an average of 302+/-205 UI/L and 285+/-149 UI/L respectively. Arterial blood ammonia averaged 172.4+/-71.3 micromol/L and glycaemia averaged 35.2+/-17.0 mg/dl. A high mortality was found in our series (41.7%). Considering that encephalopathy is the leading syndrome in these cases, the influence of ammonia on brain tissue was described. Glutamate is an excitotoxic neurotransmitter, capable to produce neuron and astrocyte damage and apoptosis. The presence of ASA could cause the onset of the mitochondrial permeability transition and the mitochondrial swelling in the astrocyte, leading to hyperammonemia. In Reye's syndrome, hyperammonemia and perhaps the increase of glutamate are the leading factors in the mechanism of brain damage and encephalopathy. Aspirin must be carefully administrated and controlled by professionals. Furthermore, parents must be informed about the risks in the use of this drug in children.

Síndrome de Reye. Descripción de un caso con especial interés en sus crisis epilépticas / Reye's syndrome. Description of a case focused on the patient's epileptic seizures

Introducción. El síndrome de Reye es una enfermedad aguda caracterizada por encefalopatía y degeneración grasa del hígado que ocurre casi exclusivamente en niños. Puede dar lugar al fallecimiento del paciente hasta en un tercio de los casos, generalmente por edema cerebral grave. La etiopatogenia de este cuadro es incierta, suele precederse de una infecciónviral generalmente por el virus de influenza o varicela. Hay estudios que han demostrado una fuerte asociación epidemiológica entre la ingestión de ácido acetilsalicílico (AAS) durante la infección viral y el desarrollo del síndrome de Reye. Caso clínico.Niña de 20 meses que desarrolla un síndrome de Reye en el contexto de cuadro viral e ingesta de AAS. La biopsia hepática es congruente con el síndrome. Presenta un estatus no convulsivo durante la fase aguda y al año desarrolla un síndrome de Lennox-Gastaut. Fallece a los 18 años por neumonía. Conclusiones. En todo paciente con clínica sugerente de síndrome de Reye, habrá que descartar errores congénitos del metabolismo que lo pueden imitar. Aunque la incidencia de este síndrome hadisminuido considerablemente en los últimos años, es importante tenerlo aún en mente, ya que un diagnóstico y tratamiento precoz y agresivo de la hipertensión cerebral disminuirá la mortalidad y las secuelas

Introduction. Reye’s syndrome is an acute disease characterised by encephalopathy and fatty degeneration of the liver that occurs almost exclusively in children. It can cause the death of the patient in up to a third of all cases, generally due to severe cerebral oedema. The aetiopathogenesis of this condition is uncertain and is usually preceded by a viral infection,generally from the influenza or varicella virus. Some studies have shown a strong epidemiological association between the ingestion of acetylsalicylic acid (ASA) during the viral infection and development of Reye’s syndrome. Case report. We describe the case of a 20-month-old female who developed Reye’s syndrome within the context of a viral infection and theingestion of ASA. A hepatic biopsy study is appropriate in this syndrome. The patient presented a non-convulsive status during the acute phase and at one year developed Lennox-Gastaut syndrome. She died from pneumonia at the age of 18 years. Conclusions. In all patients with clinical features that suggest Reye’s syndrome, inborn errors of metabolism that can mimic it must be precluded. Although the incidence of this syndrome has gone down considerably in recent years, it is important to keep it in mind as an early and aggressive diagnosis and treatment of cerebral hypertension will reduce the mortality rate and the sequelae