Mean platelet volume in children with Reye-like syndrome.

Reye-like syndrome (RLS) is considered to be a systemic disorder in which the cytokine storm plays a major role. Mean platelet volume (MPV), which is commonly used as a measure of platelet size, indicates the rate of platelet production and platelet activation. We aimed to study MPV in children with RLS. The study population consisted of 30 children with RLS and 30 healthy control subjects. White blood cell (WBC) count, aspartate transaminase (AST) and alanine transaminase (ALT) values were significantly higher and MPV values were significantly lower in patients with RLS at an early stage of illness when compared to controls. Erythrocyte sedimentation rate (ESR), C-reactive protein, AST and ALT values were significantly decreased in patients with RLS after the treatment when compared to baseline whereas MPV values were increased. MPV values were negatively correlated with ESR and WBC. In conclusion, at an early stage of RLS MPV values were lower when compared to controls.

Reye's or Reye's-like syndrome in western lowland gorilla (Gorilla gorilla gorilla).

BACKGROUND: A 15-year-old western lowland gorilla (Gorilla gorilla gorilla) died shortly after transfer to the North Carolina Zoo. METHODS: Complete blood count, serum biochemical analysis, and necropsy were performed. RESULTS: Combination of compatible clinical signs, biochemical and histopathological findings fulfilled all of the CDC definition criteria of Reye's or a Reye's like syndrome. CONCLUSIONS: This report describes a case of Reye's syndrome or Reye's-like syndrome in a non-human primate.

Carnitine palmitoyltransferase 2 deficiency: the time-course of blood and urinary acylcarnitine levels during initial L-carnitine supplementation.

Carnitine palmitoyltransferase 2 (CPT2) deficiency is one of the most common mitochondrial beta-oxidation defects. A female patient with an infantile form of CPT2 deficiency first presented as having a Reye-like syndrome with hypoglycemic convulsions. Oral L-carnitine supplementation was administered since serum free carnitine level was very low (less than 10 micromol/L), indicating secondary carnitine deficiency. Her serum and urinary acylcarnitine profiles were analyzed successively to evaluate time-course effects of L-carnitine supplementation. After the first two days of L-carnitine supplementation, the serum level of free carnitine was elevated; however, the serum levels of acylcarnitines and the urinary excretion of both free carnitine and acylcarnitines remained low. A peak of the serum free carnitine level was detected on day 5, followed by a peak of acetylcarnitine on day 7, and peaks of long-chain acylcarnitines, such as C16, C18, C18:1 and C18:2 carnitines, on day 9. Thereafter free carnitine became predominant again. These peaks of the serum levels corresponded to urinary excretion peaks of free carnitine, acetylcarnitine, and medium-chain dicarboxylic carnitines, respectively. It took several days for oral L-carnitine administration to increase the serum carnitine levels, probably because the intracellular stores were depleted. Thereafter, the administration increased the excretion of abnormal acylcarnitines, some of which had accumulated within the tissues. The excretion of medium-chain dicarboxylic carnitines dramatically decreased on day 13, suggesting improvement of tissue acylcarnitine accumulation. These time-course changes in blood and urinary acylcarnitine levels after L-carnitine supplementation support the effectiveness of L-carnitine supplementation to CPT2-deficient patients.

Reye's syndrome: patient serum alters mitochondrial function and morphology in vitro.

A direct relationship between a putative Reye's syndrome "serum factor" and generalized mitochondrial damage has been demonstrated in vitro. The clinical features of Reye's syndrome may be secondary to disrupted mitochondrial structure and a consequent impairment of energy-linked functions involving many organs.

Effect of Reye's syndrome serum on isolated chinchilla liver mitochondria.

A general impairment of liver mitochondrial enzymes is central to Reye's syndrome (RS). The respiration of isolated liver mitochondria was measured after the addition of concentrated normal serum or RS serum derived from 12 patients. RS serum stimulates oxygen consumption in isolated rat liver mitochondria. This effect is due to the oxidation of uric acid by peroxisomes contaminating the preparation and a stimulation of mitochondrial respiration (1.05 +/- 0.14 nmol of O2/min X mg of protein; control 0.30 +/- 0.08 nmol O2/min X mg). The stimulation of respiration occurs in the presence of all respiratory substrates, is dependent on the amount of serum added, and represents an uncoupling of oxidative phosphorylation. RS serum reduces ATP formation by 15-76%. The uncoupling effect correlates with the amount of free fatty acid in the serum sample and resembles the effect induced by the addition of a dicarboxylic fatty acid. Dicarboxylic fatty acids, especially long-chain dicarboxylic acids, impair ATP formation. Dicarboxylic acids were found in the serum of all RS patients and comprised as much as 54% of the total serum free fatty acids. 90% of the serum dicarboxylic acids were of 16-18 carbon lengths. The amount of dicarboxylic acids in the RS serum corresponded directly with the reduction in ATP formation by the RS serum. This demonstrates that dicarboxylic acids occur in RS and may be important in the general impairment of mitochondrial function in RS and other disorders where they are present.

[Adaptation of Biomerieux enzymatic UV ammonia on Konelab analysers]. / Adaptation de l'ammonium enzymatique UV de BioMérieux sur automates Konelab.

INTRODUCTION: Circulating ammonia in normal patients is relatively low, despite the fact that ammonia is continually produced from endogenous amino acid metabolism. The physiopathological interest of plasmatic ammonia determination lies primarily in its relationships to hepatic insufficiency (cirrhotic or neoplasic), or the diagnosis and the forecast of the Reye's syndrome. OBJECTS: This study describes an evaluation of plasmatic ammonia determination by the UV end point enzymatic method using GLDH on KONELAB(TM) analyzers. METHODS: The glutamate dehydrogenase (GLDH : EC.1.4.1.3) catalyses the reducing amination of alpha-cetoglutarate in the presence of NH(4)(+) and of NADPH, H(+) to form glutamate and NADP(+). The reduction of NADPH,H(+)'s concentration, directly proportional to ammonia rates, is evaluated at 340 nm. All the conditions were met to optimize the method, while covering a satisfying field of measurement. RESULTS AND COMMENTS: The evaluation of the modified method showed a good precision (repeatability: CV < 4 %; interserial reproducibility: CV from 2.01 to 2.93 %; Intraserial reproducibility: CV equal to 0.67%) and a very good accuracy. The field of measurement extends from 27 to 250 micromol/L, with a limit of detection (L(D)) lowered to 0.325 micromol/L. CONCLUSION: The adapted technique is simple, fast, inexpensive and especially automatizable. It is in addition reliable and chiefly more sensitive, adapting particularly to the determination of plasmatic ammonia in urgency as in routine within our laboratory.

The Measurement of Ammonia in Human Breath and its Potential in Clinical Diagnostics.

Ammonia is an important component of metabolism and is involved in many physiological processes. During normal physiology, levels of blood ammonia are between 11 and 50 µM. Elevated blood ammonia levels are associated with a variety of pathological conditions such as liver and kidney dysfunction, Reye's syndrome and a variety of inborn errors of metabolism including urea cycle disorders (UCD), organic acidaemias and hyperinsulinism/hyperammonaemia syndrome in which ammonia may reach levels in excess of 1 mM. It is highly neurotoxic and so effective measurement is critical for assessing and monitoring disease severity and treatment. Ammonia is also a potential biomarker in exercise physiology and studies of drug metabolism. Current ammonia testing is based on blood sampling, which is inconvenient and can be subject to significant analytical errors due to the quality of the sample draw, its handling and preparation for analysis. Blood ammonia is in gaseous equilibrium with the lungs. Recent research has demonstrated the potential use of breath ammonia as a non-invasive means of measuring systemic ammonia. This requires measurement of ammonia in real breath samples with associated temperature, humidity and gas characteristics at concentrations between 50 and several thousand parts per billion. This review explores the diagnostic applications of ammonia measurement and the impact that the move from blood to breath analysis could have on how these processes and diseases are studied and managed.

Free fatty acids in an animal model of Reye's syndrome.

Recent studies have indicated that viral infections, aspirin treatment and hyperammonemia are associated with Reye's syndrome. It has also been reported that free fatty acids in serum and total lipids in the liver of Reye's syndrome patients are elevated during illness. The role of the lipid changes in the development of the disorder cannot be optimally studied in human patients, because infection and aspirin ingestion occur prior to the earliest symptoms of Reye's syndrome. Effects of influenza B infection, aspirin treatment and hyperammonemia on the level of free fatty acids, total lipids and triacylglycerols in serum and liver of an animal model of Reye's syndrome are reported here. Hyperammonemia was produced in young, male ferrets either by feeding them small amounts of an arginine-deficient diet after overnight fasting or by an intraperitoneal injection of jackbean urease. The ferret model resembled Reye's syndrome in developing increased levels of individual and total serum free fatty acids, liver triacylglycerol and total lipids. The results also indicate that influenza infection or aspirin treatment, or both, while increasing the severity of encephalopathy in the deficient ferrets, did not cause a significant change in the level of serum free fatty acids. Other results suggest that elevation of serum ammonia, serum free fatty acid or liver lipids, either singly or in various combinations, does not provide conditions that can explain the rapidly developing encephalopathy in the arginine-deficient ferrets.

Reye's syndrome in adults. Diagnostic considerations.

Reye's syndrome (RS) is generally considered a childhood disease. We report our experience with RS in adults in the metropolitan Milwaukee area. Reye's syndrome was diagnosed in seven 18- to 46-year-old adults. The diagnostic criteria were as follows: viral prodrome followed by vomiting and encephalopathy without focal neurological signs, normal cerebrospinal fluid values, increased levels of serum aminotransferases (transaminase), prolonged prothrombin time, elevated blood ammonia levels, and characteristic microvesicular fatty liver and mitochondrial changes. None of the patients was hypoglycemic. The diagnosis of RS was entertained in 22 but confirmed in only seven patients. In cases of non-Reye's encephalopathy, drug ingestion presented as one of the most difficult differential diagnostic problems, which also included alcohol abuse, collagen vascular disease, and hepatitis B surface antigenemia. Clinical jaundice, distinctly uncommon in RS, was present in only one patient who presented to us in stage V coma. In adults, RS is more difficult to diagnose and should be suspected more frequently in patients with unexplained altered behavior following a viral illness and vomiting. Liver biopsy can be performed safely and is usually mandatory in adults. Patients with RS diagnosed during stage I or II coma and treated experienced an uneventful recovery.

EEG correlations with biochemical abnormalities in Reye syndrome.

A patient with Reye syndrome was studied throughout the course of the illness with continuous EEG monitoring, and these patterns were correlated with serial determinations of serum ammonia and short-chain fatty acid concentrations. There was high correlation between degree of EEG abnormality, clinical symptoms, and elevations of the short-chain fatty acids, while serum ammonia concentrations correlated poorly with the EEG and with the clinical state.

Tissue lipids in hyperammonemic encephalopathies of childhood.

Cholesterol, triglyceride, free fatty acid, and phospholipid concentrations were measured in 33 brain, liver, and adipose tissue samples obtained from 17 children who died of an acute encephalopathy associated with liver dysfunction and hyperammonemia (hyperammonemic encephalopathy). Eleven patients had Reye's syndrome, three had acute "toxic" encephalopathy (without fatty liver), two had glycogen storage disease type 1, and one had congenital hyperammonemia type 2. Hepatic triglyceride concentrations were markedly increased in Reye's syndrome, but varied from normal to increased concentrations in other hyperammonemic encephalopathies. In contrast, the acute encephalopathy could not be differentiated on the basis of clinical, laboratory, or pathologic features and the brain lipid profiles were remarkably similar among all patients studied.

Significance of positive spike burst in Reye syndrome.

We have previously reported a high incidence of 14-and 6-cps positive spike bursts in comatose patients with Reye syndrome. To further demonstrate this association, positive spike bursts were obtained in three additional cases but only in certain stages during the acute phase of illness. They varied in frequency from 7 to 13 cps, presumably reflecting the degree of slowing of the background EEG activity. A loud noise or other stimuli often precipitated the bursts, particularly when high amplitude delta waves were prominant. We believe that the presence of the positive spike bursts in comatose patients may be of diagnostic significance in Reye syndrome and that an undetermined metabolic or biochemical disturbance may be responsible for their appearance.

Short-chain fatty acids and encephalopathy of Reye's syndrome.

Plasma levels of six short-chain fatty acids (SCFA) were measured in 23 Reye's syndrome patients. In sequential measurements, only propionic acid correlated closely with neurologic severity. Although admission SCFA levels were slightly elevated, there were no significant differences between patients grouped by severity of encephalopathy. Admission SCFA did not predict neurologic outcome; also, they correlated poorly with admission blood ammonia, amino acid nitrogen, and lactate.

Short-chain organic acidemia and Reye's syndrome.

Short-chain fatty acids were determined prior to therapy in seven patients with Reye's syndrome. Elevated concentrations of propionate, butyrate, and isobutyrate were found in all patients. Isovalerate concentrations were high in three patients. In view of the fact that the administration of certain short-chain fatty acids to experimental animals results in coma, electroencephalographic changes, and fatty accumulation in the viscera, the elevations of short-chain fatty acid concentrations observed in the present study suggest that these fatty acids may play a role in the clinical manifestations of Reye's syndrome.

Hepatic and encephalopathic components of Reye's syndrome: factor analysis of admission data from 209 patients.

Factor analysis of admission data from 209 Reye's syndrome patients yielded three factors. Factor 1 was associated with encephalopathy, blood ammonia, creatinine kinase (CK), uric acid and, to a lesser extent, bilirubin. This factor was linked to the encephalopathy and hypermetabolic changes in muscle, possibly prostaglandin-mediated proteolysis. Factor 2 was associated with serum alanine aminotransferase (AlaAT) and aspartate aminotransferase (AspAT), and was identified as a hepatic lesion component. These factors correspond to two etiologic components of Reye's syndrome. Salicylate was only weakly associated with neuropathic and hypercatabolic indicators and not at all associated with the hepatic damage indicators.

Reye syndrome: serum-induced alterations in brain mitochondrial function are blocked by fatty-acid-free albumin.

Oxygen utilization and pH changes were monitored simultaneously in mitochondria isolated from rat brain. Addition of serum from four patients with Reye syndrome stimulated the resting respiratory rate, decreased respiratory control, stimulated ATPase activity, and decreased the rate of phosphorylation as measured by changes in pH. Serum from normal individuals did not have these effects. Convalescent serum from the three surviving patients showed a return of values toward normal. These changes were most marked with serum from the more deeply comatose patients. Contrary to a previous study of rat liver mitochondria, the changes were blocked by preincubation of the patients' sera with fatty-acid-free albumin. The serum factor responsible for the impairment in mitochondrial function may be a short- or medium-chain fatty acid.

Ornithine carbamoyltransferase deficiency in an adult male patient: significance of hepatic ultrastructure in clinical diagnosis.

Ornithine carbamoyltransferase (OCT) activity was deficient (8% of control) in the liver of a 21-year-old man who died after suddenly becoming comatose. Activities of other enzymes of the urea cycle in the liver were normal. There was no known prior illness or injury; the patient, however, had been taking liquid protein supplements to his diet. Hyperammonemia and orotic aciduria were present, and the concentration of lysine in the plasma was elevated. Survey of earlier reports indicates that neither the specific deficiency of hepatic OCT nor the urine and plasma findings provide a basis for definitive diagnosis of the patient's illness as primary OCT deficiency or as Reye's syndrome. Indeed, the age of the patient at onset of symptoms and the absence of any prodromal infection argue against the OCT deficiency being either primary or a sequel to Reye's syndrome. We suggest that it was secondary to mitochondrial injury caused by an unknown agent. Electron microscopic study of hepatocyte ultrastructure lends support to this view; abnormalities of the patient's mitochondria (bizarre, elongated shapes) do not resemble those seen in Reye's syndrome, nor have abnormalities been found in primary OCT deficiency.

Triglyceride and cholesterol concentrations in whole serum and in serum lipoproteins in Reye syndrome.

Triglyceride and cholesterol concentrations in whole serum and in the serum lipoprotein fractions were measured during the course of hospitalization in six patients with Reye syndrome, four of whom survived. Very low density lipoprotein (VLDL) triglycerides were significantly lower on admission than on the last day of hospitalization. However, no VLDL triglyceride value was below the normal range. Triglyceride transport was increased in low density lipoprotein (LDL) and high density lipoprotein (HDL) fractions. LDL and HDL cholesterol concentrations were low on admission and decreased further during hospitalization. The changes in LDL and HDL cholesterol concentrations were more severe among nonsurvivors. No HDL cholesterol was detected in nonsurvivors on the last day of hospitalization. These results suggest that decreased VLDL triglycerides may not play an important role in the development of fatty liver and that decreased LDL and HDL cholesterol concentrations may be of prognostic value in Reye syndrome.

Aflatoxin B1; its role in the etiology of Reye's syndrome.

Seven cases of Reye's syndrome in which aflatoxin B1 was isolated from the blood or liver or both are presented. In two cases aflatoxin B1 was found in the blood during the acute phase of the disease; a finding not previously reported. In six cases aflatoxin B1 was recovered from autopsy specimens of liver. A number of case reports linking aflatoxin B1 to Reye's syndrome have appeared in the literature but until now only one case had been reported from the United States. Aflatoxin B1 and its possible role in the etiology of Reye's syndrome is discussed. It is concluded that Reye's syndrome is the result of multiple interrelated factors.

Evidence for hypertyraminemia in Reye's syndrome.

Utilizing a specific and sensitive radioimmunoassay, palsma and urine tyramine were measured in 14 consecutive patients with liver biopsy-proven Reye's syndrome. Plasma tyrosine was measured in 11 of these patients. The results revealed significant (P less than .003) elevation in plasma (3.4 +/- .52 ng/ml) (mean +/- SEM) and urine (1.00 +/- .26 mg/24 hr) tyramine as well as plasma tyrosine (204 +/- 52.5 mumole/liter) at the onset of the disease when compared to the levels of tyramine and tyrosine in a group of hospitalized patients without hepatic disorders. Furthermore, there was a positive correlation between plasma tyramine and days in coma (r = .86; P less than .001), and between plasma tyramine and tyrosine (r = 0.80; P less than .001). These data suggest that there is s substantial disturbance of tyrosine metabolism in Reye's syndrome and that the accumulation of this amino acid and its metabolite, tyramine, may contribute to the encephalopathy of this disease.