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PubMed1985

Fatal case of pyruvate dehydrogenase deficiency.

A Japanese neonate with fatal pyruvate dehydrogenase deficiency is described. The patient lapsed into a coma shortly after birth with severe metabolic acidosis caused by accumulation of lactate and pyruvate. Hyperammonemia was also present and found to be the cause of the coma. Despite intensive treatment, the patient died at 93 hours of age. Enzyme study showed that the activity of pyruvate dehydrogenase was not detected in either the liver or the kidneys. This is the third reported case of fatal pyruvate dehydrogenase deficiency and hyperammonemia is described for the first time in this condition.

Acidosis↗

PubMed1978

Ammonia intoxication in the near-adult cat as a result of a dietary deficiency of arginine.

Near-adult cats, fasted overnight, and given a single meal of a complete amino acid diet without arginine, developed hyperammonemia and showed clinical symptoms of ammonia toxicity within 2 hours. One cat (2.7 kilograms) died 4.5 hours after ingesting only 8 grams of the diet. Since ornithine also prevented hyperammonemia, it appears that the domestic cat cannot synthesize ornithine.

Amino Acids↗

PubMed2002

Mouse model for human arginase deficiency.

Deficiency of liver arginase (AI) causes hyperargininemia (OMIM 207800), a disorder characterized by progressive mental impairment, growth retardation, and spasticity and punctuated by sometimes fatal episodes of hyperammonemia. We constructed a knockout mouse strain carrying a nonfunctional AI gene by homologous recombination. Arginase AI knockout mice completely lacked liver arginase (AI) activity, exhibited severe symptoms of hyperammonemia, and died between postnatal days 10 and 14. During hyperammonemic crisis, plasma ammonia levels of these mice increased >10-fold compared to those for normal animals. Livers of AI-deficient animals showed hepatocyte abnormalities, including cell swelling and inclusions. Plasma amino acid analysis showed the mean arginine level in knockouts to be approximately fourfold greater than that for the wild type and threefold greater than that for heterozygotes; the mean proline level was approximately one-third and the ornithine level was one-half of the proline and ornithine levels, respectively, for wild-type or heterozygote mice--understandable biochemical consequences of arginase deficiency. Glutamic acid, citrulline, and histidine levels were about 1.5-fold higher than those seen in the phenotypically normal animals. Concentrations of the branched-chain amino acids valine, isoleucine, and leucine were 0.4 to 0.5 times the concentrations seen in phenotypically normal animals. In summary, the AI-deficient mouse duplicates several pathobiological aspects of the human condition and should prove to be a useful model for further study of the disease mechanism(s) and to explore treatment options, such as pharmaceutical administration of sodium phenylbutyrate and/or ornithine and development of gene therapy protocols.

Animals↗

PubMed1989

The importance of glyoxylate and other glycine precursors in the hepatic and renal conjugation of benzoate in normal and hyperammonemic mice.

Benzoate conjugation, represented by hippurate synthesis, was measured in hepatocytes isolated from normal and sparse-fur (spf) mutant mice, with X-linked ornithine transcarbamylase deficiency, to compare the effects of glyoxylate and piridoxylate (a hemiacetal of glyoxylate and pyridoxine), substituted for glycine. Various amino acid precursors of glycine described in the literature, including serine, threonine, glutamine, and glutamate, were studied in a similar manner. The role of glyoxylate and piridoxylate was also assessed in the renal cortex, in comparison with liver homogenates from normal and hyperammonemic mice. The results indicate the importance of glyoxylate and piridoxylate to completely substitute for glycine (96-115%) in isolated hepatocytes of spf/Y mice, as compared with 53-69% (p less than 0.05) in normal +/Y controls. The mean value of amino acid precursors to substitute for glycine in spf mice was serine 51%, threonine 29% (p less than 0.05), and glutamine 9%. In normal mice, only serine (21%) (p less than 0.01) partly substituted for glycine, whereas threonine, glutamine and glutamate gave negative values of net hippurate synthesis. The specific activity of renal cortex for hippurate synthesis from glycine, glyoxylate and piridoxylate was 3-4 times that of liver homogenates (p less than 0.01 - less than 0.001). A scheme for the transamination of glyoxylate by alanine is presented. Besides alanine, the excess of glycine, serine, and threonine is readily deaminated in the body to take part in gluconeogenic reactions, thus contributing to hyperammonemia. The cumulative effect of benzoate conjugation to drain these ammoniagenic precursors through glycine may be the basis of its therapeutic effect in hyperammonemia.

Ammonia↗

PubMed2005

Genetic ablation of Rhbg in the mouse does not impair renal ammonium excretion.

NH(4)(+) transport by the distal nephron and NH(4)(+) detoxification by the liver are critical for achieving regulation of acid-base balance and to avoid hyperammonemic hepatic encephalopathy, respectively. Therefore, it has been proposed that rhesus type B glycoprotein (Rhbg), a member of the Mep/Amt/Rh NH(3) channel superfamily, may be involved in some forms of distal tubular acidosis and congenital hyperammonemia. We have tested this hypothesis by inactivating the RHbg gene in the mouse by insertional mutagenesis. Histochemical studies analyses confirmed that RHbg knockout (KO) mice did not express Rhbg protein. Under basal conditions, the KO mice did not exhibit encephalopathy and survived well. They did not exhibit hallmarks of distal tubular acidosis because neither acid-base status, serum potassium concentration, nor bone mineral density was altered by RHbg disruption. They did not have hyperammonemia or disturbed hepatic NH(3) metabolism. Moreover, the KO mice adapted to a chronic acid-loading challenge by increasing urinary NH(4)(+) excretion as well as their wild-type controls. Finally, transepithelial NH(3) diffusive permeability, or NH(3) and NH(4)(+) entry across the basolateral membrane of cortical collecting duct cells, measured by in vitro microperfusion of collecting duct from KO and wild-type mice, was identical with no apparent effect of the absence of Rhbg protein. We conclude that Rhbg is not a critical determinant of NH(4)(+) excretion by the kidney and of NH(4)(+) detoxification by the liver in vivo.

Acidosis, Renal Tubular↗

PubMed1996

Comparison of the metabolic disturbances caused by end-to-side and side-to-side portacaval shunts.

Portacaval shunting causes liver atrophy, hyperammonemia, and hepatic encephalopathy. A fundamental question is whether the changes, especially those to brain, are permanent. To answer this, it is necessary to have a model whereby a portacaval shunt can be created for a period of time and then the normal pattern of circulation to the liver restored at will. An end-to-side shunt, the most extensively studied model of liver dysfunction, is permanent. However, a side-to-side shunt can be constructed that results in a somewhat different pattern of circulation but with the potential to be reversed. The purpose of the present study was to compare the severity of the metabolic disturbances caused by the two models. Rats with an end-to-side shunt, a side-to-side shunt, or sham operation were prepared and studied after 14-19 days. Both models of shunting caused the same degree of liver atrophy, hyperammonemia, and indistinguishable disturbances in the amino acid content of plasma and brain. Furthermore, both models produced the same degree of cerebral depression as measured by glucose consumption.

Amino Acids↗

PubMed2006

Surgical shunt closure via the lumen of an intrahepatic portal aneurysm.

BACKGROUND/AIMS: A surgical shunt closure via the lumen of an intrahepatic portal aneurysm was successfully performed in a 70-year-old Japanese woman with hepatic encephalopathy due to hyperammonemia. She had a 4-month history of repeated hepatic encephalopathy which persisted after treatment with oral medicine. Color Doppler ultrasonography and computed tomography revealed a cystic peripheral portal aneurysm, 4 cm in diameter, connecting the posterior branch of the portal vein to the short hepatic vein in the right lobe. METHODS: While performing the Pringle maneuver and clamping the inferior vena cava below the liver, the wall of the portal aneurysm was opened, and the site of inflow from the portal vein and the site of outflow to the hepatic vein via the lumen of the portal aneurysm were closed with interrupted sutures. RESULTS: The patient's postoperative course was uneventful, and she was discharged 12 days after surgery. 12 months after surgery, she had no recurrence of hyperammonemia or hepatic encephalopathy. CONCLUSION: Surgical shunt closure via the lumen of a portal aneurysm can be performed safely, easily, and completely with good vision.

Aged↗

PubMed1985

Adaptation of hepatic ammonia metabolism after chronic valproate administration in epileptics treated with phenytoin.

The effects of phenytoin (PHT) on the modifications of ammonia (NH+4) metabolism caused by sodium valproate (VPA) are here studied in order to identify the drug combinations susceptible of evoking stuporous states in epileptics, a rare condition attributed to a hyperammonemic encephalopathy induced by VPA. During chronic treatment with PHT or VPA-PHT, the acute injection of VPA increases the kidney's output of NH+4. During chronic PHT treatments, the acute injection of VPA modifies the liver's NH+4 metabolism and the arterial hyperammonemia is high (mean = 90 mumol/l). During chronic VPA-PHT treatments, the acute injection of VPA does not affect the hepatic NH+4 metabolism, suggesting that adaptation occurs, and the arterial hyperammonemia is moderate (mean = 60 numol/l). Disturbances of the hepatic adaptive mechanisms may explain certain complications observed during multiple-drug regimens.

Adaptation, Physiological↗

PubMed1982

Serum enzyme alterations in arginine-deficient, influenza-infected ferrets: a potential animal model of Reye's syndrome.

Young male ferrets developed hyperammonemia and encephalopathy soon after eating a diet lacking arginine. Because of this characteristic and their known susceptibility to influenza infections, they were further tested as an animal model for Reye's syndrome (RS), a childhood disorder which sometimes develops following influenza and which is characterized in part by encephalopathy, hyperammonemia, and elevated serum transaminase levels. Either the deficiency or infection alone resulted in minor elevations of serum ornithine carbamyl transferase (S-OCT) activities and together resulted in substantial elevations. These and associated alterations are discussed in relationship to the metabolic disorders occurring in RS.

Ammonia↗

PubMed1984

Arginine, an indispensable amino acid for patients with inborn errors of urea synthesis.

The role of arginine as an essential amino was evaluated in four children with one of the deficiencies of carbamyl phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthetase, and argininosuccinase. Within 15-68 h after arginine deprivation nitrogen accumulated as ammonium or glutamine or both, but glutamine was quantitatively the largest nitrogen accumulation product. Concomitantly plasma and urinary urea levels decreased. Resumption of arginine intake (or citrulline in the case of ornithine transcarbamylase deficiency) promptly led to correction of the hyperammonemia, hyperglutaminemia and hypoargininemia. Ornithine was an unsatisfactory substitute for arginine. Arginine deprivation did not interfere with carbamyl phosphate synthesis as manifested by orotic aciduria. It is concluded that arginine is an indispensable amino acid for children with inborn errors of ureagenesis and its absence results in the rapid onset of symptomatic hyperammonemia.

Amino Acid Metabolism, Inborn Errors↗

PubMed1986

Cerebral glucose metabolism after portacaval shunting in the rat. Patterns of metabolism and implications for the pathogenesis of hepatic encephalopathy.

The regional cerebral metabolic rate for glucose was measured in normal and portacaval shunted rats and the effects of unilateral carotid infusions of "threshold" amounts of ammonia were assessed. 8 wk after shunting the glucose metabolic rate was increased in all 20 brain regions sampled. Effects on subcortical and phylogenetically older regions of the brain were most pronounced with a 74% increase observed in the reticular formation at the collicular level. Increases in the cerebral cortex ranged from 12 to 18%. Unilateral infusions of ammonia did not affect behavior but altered the electroencephalogram and selectively increased the glucose metabolic rate in the thalamus, hypothalamus, and substantia nigra in half of the animals, a pattern similar to that seen after a portacaval shunt, suggesting hyperammonemia as the cause of postshunt increases in glucose metabolism. Visual inspection of autoradiograms, computed correlation coefficients relating interregional metabolism, and principal component analysis suggest that normal cerebral metabolic and functional interrelationships are altered by shunting. Ammonia stimulation of the hypothalamic satiety centers may suppress appetite and lead to cachexia. Reductions in the ammonia detoxification capacity of skeletal muscle may increase the probability of developing future episodes of hyperammonemia, perpetuating the process. Direct effects of ammonia on specific brain centers such as the dorsomedial hypothalamus and reticular activating system may combine with global disruptions of cerebral metabolic-functional relationships to produce the protean manifestations of portal-systemic encephalopathy.

Acetates↗

PubMed1994

Prenatal counseling in heterozygotes for ornithine transcarbamylase deficiency.

X-linked ornithine transcarbamylase deficiency (OTCD) often leads to fatal neonatal hyperammonemia in affected males (hemizygotes). In prenatal management of subsequent pregnancies, families carrying female fetuses are often reassured of the low risk of clinically overt disease. We suggest that such reassurance may be misleading. While OTCD heterozygotes may show no symptoms or only mild protein intolerance, the clinical course in a fraction of children can include manifestations similar to those in affected males. We present three cases of symptomatic and previously undiagnosed OTCD heterozygotes to illustrate the potential severity of this condition. Significant improvement in function and growth followed diagnosis and treatment; however, two of the three children remain significantly developmentally delayed. While a quantitative risk estimate cannot be derived from these data, the cases are indicative of an adverse outcome in manifesting heterozygotes. Accordingly, OTCD carrier families should be counseled regarding the possibility of significant hyperammonemia, neurologic deficit, and the need for pharmacologic and dietary intervention in their heterozygote daughters.

Adolescent↗

PubMedDate not supplied

Complications of essential amino acid hyperalimentation in children with acute renal failure.

The metabolic effects of intravenous hyperalimentation, using an essential amino acid (EAA) and glucose solution, were evaluated in 2 children with acute renal failure. Hyperammonemia and hyperchloremic metabolic acidosis associated with elevated plasma methionine and depressed plasma citrulline, ornithine, arginine, and histidine levels complicated the nutritional therapy. Initial infusion of a complete amino acid (CAA) solution was not associated with these aberrations and reintroduction of a CAA solution after the EAA trial resulted in a progressive amelioration of or complete recovery from these metabolic disturbances. It is likely that the hyperammonemia was due to an arginine deficiency, while excess methionine and presumably sulfate production may have contributed to the hyperchloremic metabolic acidosis in these two children.

Acidosis↗

PubMedDate not supplied

Plasma ammonia levels in preterm infants receiving parenteral nutrition with crystalline L-amino acids.

In order to investigate the severity and incidence of hyperammonemia in preterm infants receiving total parenteral nutrition (TPN) with crystalline L-amino acids having high arginine content (Travasol), we determined the plasma ammonia (PA) levels in a group of 29 preterm infants on TPN, weekly and 1 wk posttherapy. Their mean gestational age was 29.9 +/- 2.6 wk and mean birth weight 1208 +/- 262 g. Thirty five blood samples obtained from 15 preterm infants not on TPN with mean gestational age 32.2 +/- 1.9 wk and a birth weight of 1495 +/- 161 g served as a control. In the parenteral nutrition group the mean PA level (140 +/- 58 micrograms/100 ml) was significantly higher (p less than 0.001) than that in the same group one week post TPN (97 +/- 34 micrograms/100 ml) and in the control group (86 +/- 35 micrograms/100 ml). The incidence of hyperammonemia (greater than 160 micrograms/100 ml) was 30% in the TPN group versus 3% in the controls (p less than 0.01). Maximal PA level during that treatment was 405 versus 216 micrograms/100 ml 1 wk post-TPN versus 163 micrograms/100 ml in the controls. The data show a significant increase in PA levels in preterm infants receiving TPN with Travasol, possibly because of its high glycine content.

Ammonia↗

PubMedDate not supplied

Complication of parenteral nutrition composed of essential amino acids and histidine in adults with renal failure.

This is a case report on six patients with hyperammonemia that developed while they were receiving total parenteral nutrition (TPN) as a component of renal failure therapy. Clinically, the hyperammonemia presented as mental status changes in all six cases. Four of the six patients with renal failure initially received 400 mL Amiyu in 1400 mL 17% glucose (total = 1800 mL TPN-A) administered over each 24-hour period. Two patients had been placed on 400 mL complete amino acid in 1400 mL 17% glucose (total = 1800 mL TPN-C over each 24-hour period) prior to therapy with TPN-A. Approximately 3 weeks after initiation of TPN therapy with TPN-A, episodes of mental status changes of increasing duration and paroxysms were documented in five of the six patients. In one of the patients receiving TPN-C prior to TPN-A therapy, toxicity was clinically evident only 4 days after initiation of TPN-A. Serum ammonia levels were obtained and found to be elevated in the acute (ie, presenting) stage in all patients. With the discontinuance of TPN-A, ammonia levels normalized uniformly. Mental status also improved in all cases except for the patient with rapid clinical presentation who died 2 weeks after first evidence of clinical toxicity. In cases 1, 2, and 6, serum amino acid analysis in the acute phase showed reduced levels of ornithine and citrulline, the substrate and product, respectively, of condensation with carbamyl phosphate at its entry into the urea cycle. Moreover, levels of arginine, precursor to ornithine, were found to be elevated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2002

Neonatal presentation of ventricular tachycardia and a Reye-like syndrome episode associated with disturbed mitochondrial energy metabolism.

BACKGROUND: Hyperammonemia, hypoglycemia, hepatopathy, and ventricular tachycardia are common presenting features of carnitine-acylcarnitine translocase deficiency (Mendelian Inheritance in Man database: *212138), a mitochondrial fatty acid oxidation disorder with a lethal prognosis. These features have not been identified as the presenting features of mitochondrial cytopathy in the neonatal period. CASE PRESENTATION: We describe an atypical presentation of mitochondrial cytopathy in a 2 day-old neonate. She presented with a Reye-like syndrome episode, premature ventricular contractions and ventricular tachycardia. Initial laboratory evaluation exhibited a large amount of 3-methylglutaconic acid on urine organic acid analysis, mild orotic aciduria and a nonspecific abnormal acylcarnitine profile. The evaluation for carnitine-acylcarnitine translocase deficiency and other fatty acid oxidation disorders was negative. The patient later developed a hypertrophic cardiomyopathy and continued to be affected by recurrent Reye-like syndrome episodes triggered by infections. A muscle biopsy exhibited signs of a mitochondrial cytopathy. During the course of her disease, her Reye-like syndrome episodes have subsided; however, cardiomyopathy has persisted along with fatigue and exercise intolerance. CONCLUSIONS: This case illustrates that, in the neonatal period, hyperammonemia and ventricular tachycardia may be the presenting features of a lethal carnitine-acylcarnitine translocase deficiency or of a mitochondrial cytopathy, associated with a milder clinical course. This association broadens the spectrum of presenting phenotypes observed in patients with disturbed mitochondrial energy metabolism. Also, the presence of 3-methylglutaconic aciduria suggests mitochondrial dysfunction and mild orotic aciduria could potentially be used as a marker of mitochondrial disease.

Biomarkers↗

PubMed1976

Ornithine transcarbamylase deficiency: enzyme studies on a further case and a method of diagnosis using plasma enzyme ratios.

The activities of the urea cycle enzymes in the liver of a female patient with hyperammonemia were determined (Table 1). Ornithine transcarbamylase (OTC, EC. 2.1.3.3) was reduced to 5-10% of normal and the residual enzyme showed an apparent Kmorn of 0.69 (normal 0.37 +/- 0.10) mmol liter. The pH dependence was normal. The patient's mother also showed hyperammonemia but was not clinically affected. Consideration of the genetics of the disease suggested that many female patients should have a mixture of normal and mutant enzymes. Electrophoresis of the patient's liver extract showed an additional band of OTC activity probably due to this mutant enzyme. The ratio of plasma glutamate-pyruvate transaminase to OTC was abnormal in four clinically affected patients with OTC deficiency (Fig. 4B) but not in two of their mothers without clinical signs.

Alanine Transaminase↗

PubMed1986

Waste nitrogen excretion via amino acid acylation: benzoate and phenylacetate in lysinuric protein intolerance.

Benzoate and phenylacetate improve prognosis in inherited urea cycle enzyme deficiencies by increasing waste nitrogen excretion as amino acid acylation products. We studied metabolic changes caused by these substances and their pharmacokinetics in a biochemically different urea cycle disorder, lysinuric protein intolerance (LPI), under strictly standardized induction of hyperammonemia. Five patients with LPI received an intravenous infusion of 6.6 mmol/kg L-alanine alone and separately with 2.0 mmol/kg of benzoate or phenylacetate in 90 min. Blood for ammonia, serum urea and creatinine, plasma benzoate, hippurate, phenylacetate, phenylacetylglutamine, and amino acids was obtained at 0, 120, 180, and 270 min. Urine was collected in four consecutive 6-h periods. Alanine caused hyperammonemia: maximum increase 107, 28-411 microM (geometric mean, 95% confidence interval); ammonia increments were nearly identical after alanine + benzoate (60, 17-213 microM) and alanine + phenylacetate (79, 13-467 microM) (NS). Mean plasma benzoate was 6.0 mM when extrapolated to the end of alanine + benzoate infusions; phenylacetate was 4.9 mM at the end of alanine + phenylacetate. Transient toxicity (dizziness, nausea, vomiting) occurred in four patients at the end of combined infusions, and we suggest upper therapeutic plasma concentrations of 4.5 mM for benzoate and 3.5 mM for phenylacetate. Benzoate and phenylacetate then decreased following first-order kinetics with t1/2S of 273 and 254 min, respectively. Maximal plasma hippurate (0.24, 0.14-0.40 mM) was lower than maximal phenylacetylglutamine (0.48, 0.22-1.06 mM, p = 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)

Acylation↗