Dihydrolipoamide dehydrogenase deficiency: a still overlooked cause of recurrent acute liver failure and Reye-like syndrome.

The causes of Reye-like syndrome are not completely understood. Dihydrolipoamide dehydrogenase (DLD or E3) deficiency is a rare metabolic disorder causing neurological or liver impairment. Specific changes in the levels of urinary and plasma metabolites are the hallmark of the classical form of the disease. Here, we report a consanguineous family of Algerian origin with DLD deficiency presenting without suggestive clinical laboratory and anatomopathological findings. Two children died at birth from hepatic failure and three currently adult siblings had recurrent episodes of hepatic cytolysis associated with liver failure or Reye-like syndrome from infancy. Biochemical investigation (lactate, pyruvate, aminoacids in plasma, organic acids in urine) was normal. Histologic examination of liver and muscle showed mild lipid inclusions that were only visible by electron microscopy. The diagnosis of DLD deficiency was possible only after genome-wide linkage analysis, confirmed by a homozygous mutation (p.G229C) in the DLD gene, previously reported in patients with the same geographic origin. DLD and pyruvate dehydrogenase activities were respectively reduced to 25% and 70% in skin fibroblasts of patients and were unresponsive to riboflavin supplementation. In conclusion, this observation clearly supports the view that DLD deficiency should be considered in patients with Reye-like syndrome or liver failure even in the absence of suggestive biochemical findings, with the p.G229C mutation screening as a valuable test in the Arab patients because of its high frequency. It also highlights the usefulness of genome-wide linkage analysis for decisive diagnosis advance in inherited metabolic disorders.

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.

Mortality in dioxin-exposed mice infected with influenza: mitochondrial toxicity (reye's-like syndrome) versus enhanced inflammation as the mode of action.

Increased mortality following influenza A infection was reported in B6C3F1 mice exposed to a low (0.01 micro g/kg) dose of dioxin. However, mortality was not associated with increased viral load and antibody titers to the virus were not decreased at doses of TCDD < or = 10 micro g/kg, suggesting that viral overgrowth, secondary to immunosuppression, was not the proximate cause of death. We tested the hypothesis that mitochondrial toxicity and dysfunction, similar to Reye's syndrome (RS) in humans, is responsible for increased mortality in dioxin-exposed, infected B6C3F1 female mice, based on similarities in the biochemical and immunological events that occur in RS and in TCDD-exposed animals. Endpoints were also included to test the hypothesis that increased pulmonary inflammation following dioxin exposure, in the absence of mitochondrial toxicity, was associated with increased mortality. Dose-related effects of TCDD alone, infection with influenza A alone, and combined TCDD exposure/influenza infection were evaluated. Mice were given a single ip injection of 0, 0.001, 0.01, 0.1, or 1.0 micro g TCDD/kg, 7 days before infection by intranasal instillation of an estimated LD(10-20) of influenza A Hong Kong/8/68 (H3N2) and were terminated 1, 7, and 10 days after infection. Serum, bronchoalveolar lavage fluid (BALF), and lung tissue were collected for various measurements, including clinical chemistries, cell counts, cytokine analysis, and viral titers. Exposure to < or = 1.0 micro g TCDD/kg did not increase mortality; virus titers were similar at all doses of TCDD and there was no dioxin-related effect on serum NH(3) or glucose concentrations, two prominent indicators of the altered mitochondrial oxidative metabolism typically observed in RS. A study was therefore conducted over a wider range of TCDD doses. A single injection of 0, 0.025, 0.5, or 10 micro g TCDD/kg preceded infection by 7 days; subgroups of noninfected control and highest dose group (10 micro g TCDD/kg) mice were also evaluated for biochemical and immunological endpoints on the equivalent of infection day 4 to provide baseline data. Five days after infection the same endpoints described above were evaluated. The 10 micro g TCDD/kg dose increased mortality, but once again did not increase virus titer; as in previous experiments, serum biochemistry endpoints did not support mitochondrial dysfunction. These results suggest that RS is an unlikely explanation for increased influenza mortality in TCDD-exposed mice. Rather, constituents in BALF implicate increased pulmonary inflammation as the mode of TCDD action.

[Therapeutic effect of hepatoprotectors in experimental Reye syndrome]. / [Gepatoprotektory okazyvaiut lechebnoe deistvie pri éksperimental'nom sindrome Reie]

Maxar and legalon--hepatoprotectors containing polyphenols--exhibit a therapeutic effect with respect to the experimental Reye's syndrome induced in rats by intraperitoneal injections of 4-pentenoic acid. Maxar restores the activity of enzymes of the hepatic origin, normalizes the content of bilirubin, glucose, phenols, and malonic aldehyde in the blood serum, stimulates the production of ketone bodies and ammonia detoxication, and improves the histologic structures of liver and cortex. Legalon also decreases the structural-metabolic disorders accompanying the Reye's syndrome, but to as lower ewxtent.

Epidemiology of Reye's syndrome, United States, 1991-1994: comparison of CDC surveillance and hospital admission data.

This investigation describes the epidemiology of Reye's syndrome (RS) during 1991-1994 and compares two different sources of information in the United States. Estimates of the incidence of RS from the Centers for Disease Control and Prevention (CDC) are compared with hospital inpatient data from approximately one third of the hospitals from HCIA, Inc. During 1991-1994, 48 RS cases were reported to the CDC and 93 RS hospitalizations based on HCIA data. When the HCIA data are extrapolated to the US population, there were an estimated 284 hospitalizations. Cases reported from both data sources were similar in distribution by onset, age, and sex. CDC data probably underestimate the incidence of RS due to incomplete reporting and HCIA data may overestimate it because not all cases were known to meet the CDC case definition. The true annual incidence of RS during the study years was probably between 0.2 and 1.1 cases per million population <18 years of age.

Reye's syndrome in the United States from 1981 through 1997.

BACKGROUND: Reye's syndrome is characterized by encephalopathy and fatty degeneration of the liver, usually after influenza or varicella. Beginning in 1980, warnings were issued about the use of salicylates in children with those viral infections because of the risk of Reye's syndrome. METHODS: To describe the pattern of Reye's syndrome in the United States, characteristics of the patients, and risk factors for poor outcomes, we analyzed national surveillance data collected from December 1980 through November 1997. The surveillance system is based on voluntary reporting with the use of a standard case-report form. RESULTS: From December 1980 through November 1997 (surveillance years 1981 through 1997), 1207 cases of Reye's syndrome were reported in patients less than 18 years of age. Among those for whom data on race and sex were available, 93 percent were white and 52 percent were girls. The number of reported cases of Reye's syndrome declined sharply after the association of Reye's syndrome with aspirin was reported. After a peak of 555 cases in children reported in 1980, there have been no more than 36 cases per year since 1987. Antecedent illnesses were reported in 93 percent of the children, and detectable blood salicylate levels in 82 percent. The overall case fatality rate was 31 percent. The case fatality rate was highest in children under five years of age (relative risk, 1.8; 95 percent confidence interval, 1.5 to 2.1) and in those with a serum ammonia level above 45 microg per deciliter (26 micromol per liter) (relative risk, 3.4; 95 percent confidence interval, 1.9 to 6.2). CONCLUSIONS: Since 1980, when the association between Reye's syndrome and the use of aspirin during varicella or influenza-like illness was first reported, there has been a sharp decline in the number of infants and children reported to have Reye's syndrome. Because Reye's syndrome is now very rare, any infant or child suspected of having this disorder should undergo extensive investigation to rule out the treatable inborn metabolic disorders that can mimic Reye's syndrome.

[Reye syndrome: a case study in a Cuban provincial hospital from 1990 to 1996]. / Síndrome de Reye: estudio de la casuística de un hospital provincial cubano entre 1990 y 1996.

INTRODUCTION: Reye's syndrome is a metabolic encephalopathy of infancy which is often fatal. Epidemiological studies have shown associated factors including having taken Aspirin for viral illness. Some patients with this disorder may have preexisting organic acidemia such as dicarboxylic aciduria. OBJECTIVE: To study the behavior of Reye's syndrome in a group of patients during the years 1990-1996 in a provincial paediatric hospital and review variables such as age, sex, race, prodromal illness, previous consumption of Aspirin, hospital stay, mortality, diagnosis of dicarboxylic aciduria, etc. PATIENTS AND METHODS: We selected patients with Reye's syndrome seen during the period mentioned and considered the above variables. RESULTS: All 10 patients seen with Reye's syndrome were boys. Their ages were between 3 months and 2 years. Most (nine) of the patients were Caucasian. All patients had influenza as the prodromal illness, and all took Aspirin as an antipyretic. There was considerable variation in the length of their stay in the hospital. In our series there was a high mortality and only two patients survived. One boy had dicarboxylic aciduria. CONCLUSIONS: The fatal character of Reye's syndrome has been shown, as has its relation to the use Aspirin. In our environment there seems to be a tendency for Caucasian boys to be affected.

Investigation of an epidemic of Reye's syndrome in northern region of India.

OBJECTIVE: To determine the extent, epidemiological and clinical features of an epidemic of non-inflammatory encephalopathy in northern region of India. DESIGN: Surveillance of referred cases having unconsciousness after a short bout of fever during October and November 1997. Case control study in 7 most affected villages. METHODS: Active case finding was done to assess the extent and severity of the epidemic by interviewing health professionals and by reviewing mortality records in 10 districts of Haryana, Punjab and Chandigarh. A house to house survey was conducted in seven most affected villages. A case was defined as any child of less than 15 years of age, who had prodromal fever followed by vomiting and unconsciousness with subsequent recovery or death. Two age and sex matched controls who had fever without unconsciousness were taken for each case, one from nearby house and another staying furthest from the affected house. These groups were compared for various epidemiologic factors, clinical features and treatment pattern. Residual medicines used by affected patients were tested for presence of salicylate. Local village practitioners were interviewed for their knowledge and attitude towards use of aspirin in a febrile child. RESULTS: Information regarding 129 affected children (M: F=1 : 1) could be obtained. Age ranged between 1 to 12 years (mean 5.8 years). Most were from rural or semi-suburban areas. Attack rate was 5.4/1000 and case fatality rate was 72%. Multiple sibs were affected in 9.3%. History of fever was reported by 83%, vomiting preceding unconsciousness by 83% and abnormal behavior by 65%. Abnormal posturing was reported in 55%. Seventeen (61%) of 28 samples had IgM antibodies in serum/CSF against measles. Twelve (36%) of 33 serum samples tested positive for Varicella zoster virus. None gave history of aspirin intake and 10 samples of residual drugs did not contain salicylate. However, 6 out of 19 blood samples taken from affected patients contained salicylate. Environmental factors were in favor of Japanese encephalitis (JE) but brain biopsy and serology disproved it. Based on earlier report of JE from this area, the cases in present epidemic were being reported as JE before this study was undertaken. Intensive fogging with malathion was being undertaken as antimosquito measure, specially around the affected houses. Local village practitioners (n = 37) were unaware of contraindications of aspirin in a febrile child. CONCLUSION: Measles and varicella zoster emerged as the probable etiologies for the viral prodrome precipitating these cases of Reye's syndrome. Aspirin might have a contributory role. Malathion is another putative cofactor.

Effects of antipyretics on mortality due to influenza B virus in a mouse model of Reye's syndrome.

OBJECTIVES: To determine the effects of acetylsalicylic acid (ASA) and acetaminophen on mortality due to influenza B infection in neonatal and weanling mice, as well as any synergistic, antagonistic or indifferent effects of the combined antipyretic and virus on mortality in mice pretreated with low doses of an industrial surfactant, Toximul MP8, which has been shown to reproduce many of the features of Reye's syndrome. In vitro studies were done to determine whether ASA or acetaminophen altered the normal, interferon-mediated antiviral responses of mammalian cells. The involvement of ASA or other commonly used xenobiotics in the induction of Reye's syndrome following virus illness has not been resolved; to do so, and to elucidate the underlying metabolic mechanism, requires these studies in an animal model. DESIGN: Prospective animal study. ANIMALS: Newborn (945) and weanling (840) Swiss white mice, divided into 12 subgroups. INTERVENTIONS: Some groups received Toximul MP8 before inoculation with a dose of mouse-adapted human influenza B that produces 30% mortality (LD30); after infection, each subgroup received either placebo, ASA or acetaminophen. Mortality counts were taken daily. The in vitro effects of the antipyretics on interferon response were determined using standard virology techniques. OUTCOME MEASURE: Mortality, analyzed by survival curves (log rank test) or cumulative daily mortality (chi 2 analysis). Plaque-reducing dose (PRD50) was used to determine the outcome of the in vitro analyses. RESULTS: In neonatal mice, only subgroups given combined treatment with acetaminophen and Toximul MP8 had a statistically significant higher mortality rate than with the mice given influenza B alone. In weanling mice, it appeared that ASA shortened the time until death; however, this difference was not statistically significant. In vitro studies demonstrated that both ASA and acetaminophen decreased the interferon-induced antiviral responses of cultured mammalian cells. CONCLUSION: Antipyretics have the potential to exacerbate the consequences of a viral infection, although the specific effects are subtle and appear to be age-related.

Recognizing a case of Reye's syndrome.

Although the incidence of Reye's syndrome is declining, it remains a deadly disease. Early recognition and initiation of supportive measures can decrease the mortality rate from this disorder. Glucose levels should be maintained and electrolyte imbalances and coagulopathies should be corrected in patients with early Reye's syndrome. Comatose patients require specialized care at a tertiary care facility that has the capability to prevent and treat intracranial hypertension. Survivors of Reye's syndrome may have subtle neuropsychologic deficits but generally recover very well considering the gravity of the disease.

Reye's syndrome in the British Isles: report for 1990/91 and the first decade of surveillance.

The Reye's syndrome (RS) surveillance scheme for the British Isles, jointly organised by the British Paediatric Association and the PHLS Communicable Disease Surveillance Centre, was established in 1981. In the ten years that have followed, there has been a gradual decline in the number, and the age, of cases reported. However, the proportion of cases whose diagnosis was subsequently revised to that of an inherited metabolic disorder, has increased. These trends have been influenced by the change from 'passive' to 'active' case ascertainment in 1986; the aspirin warning issued by the Committee on Safety of Medicines in June 1986; the 1989 influenza epidemic; and the increasing awareness of conditions that mimic RS, particularly inherited metabolic disorders involving defects of fatty acid oxidation. The cases reported in 1990/91 showed the lowest annual incidence recorded so far and a median age of less than ten months (compared with 15 months in the first six years of surveillance). There was a reduction in the case fatality rate in 1990/91 (although still high at 38%) but it is of concern that two children had had pre-admission exposure to aspirin. Parents should be kept aware of the dangers of giving aspirin preparations to children with feverish illnesses.

[Neuropathological analysis of 8 cases of clinically diagnosed Reye syndrome]. / Analiza neuropatologiczna w 8 przypadkach klinicznie rozpoznanego zespolu Reye'a.

Authors discuss the possible etiopathogenesis of Reye syndrome (RS) on the base of eight own cases presented in this paper and others previously described. The febrile infection was observed on the beginning of the disease in all actually analysed cases and was followed by symptoms of acute damage of liver and brain. The central nervous system lesions present the changes increasing with time from brain oedema to the necrosis of nerve tissue. The oedematous changes could be recognized as a principal cause of unconsciousness and even of coma in RS. When the etiology of RS remain unknown the clinico-pathological observations of such cases incline to formulate three questions: Is an genetically conditioned background necessary which facilitate toxic or infectious factors to induce the RS? Is the etiology of RS only genetically conditioned? Is an specific viral infection the cause of RS?

Síndrome de Reye : Informe de un caso en adultos

Se describe el caso de una mujer joven atendida en el hospital San Ignacio (Santa Fe de Bogotá), con diagnostico post mortem de síndrome de Reye. Seguidamente, se revisan y discuten los aspectos fisiopatológicos y los concernientes al diagnóstico y la terapéutica.

Reye syndrome surveillance--United States, 1989.

Reye syndrome (RS) is an acute illness that occurs almost exclusively in children; it is characterized clinically by profuse vomiting and neurologic dysfunction, sometimes progressing to delirium, coma, and death. Continuous national surveillance for RS was established in December 1976. This report summarizes RS cases for the 1989 surveillance year (December 1, 1988-November 20, 1989).

Reye and Reye-like syndromes: results of a pilot study in Peninsular Malaya, 1986.

A pilot epidemiologic study of all cases of Reye and Reye-like syndromes was undertaken at 8 representative major hospitals in Peninsular Malaya from January 1st to December 31st 1986. The cases were classified as definitive Reye's syndrome, clinical Reye's syndrome and encephalo-hepatopathies. Less than 50% of cases reviewed fulfilled the National Center for Disease Control criteria for clinical Reye's syndrome. Causes of Reye-like syndromes/encephalo-hepatopathies included fulminant hepatitis, Japanese B encephalitis, dengue, septicaemia, and complex febrile fits. It was not possible to differentiate clinical Reye's syndrome from the other encephalo-hepatopathies by either the clinical features (except for jaundice) or biochemical parameters. Liver biopsy is necessary for a definitive diagnosis of Reye's syndrome in Malaysia, because of the high prevalence of Reye-like diseases. The mortality rate in the 2 groups of patients is similar. Ingestion of salicylates was not found to be significantly associated with Reye and Reye-like syndromes in this study.