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PubMed1989

In vivo 31P NMR spectroscopy of energy rich phosphates in the brain of the hyperammonemic rat.

Hyperammonemia is a major contributing factor to the neurological abnormalities observed in hepatic encephalopathy and in congenital defects of ammonia detoxication. In rats variable changes in labile energy rich phosphates in the brain have been observed in hyperammonemia using biochemical methods. Using 31P-NMR spectroscopy however no significant changes of the relative concentrations of the energy rich phosphates alpha, beta and gamma-ATP, phosphocreatine, inorganic phosphate and the pH were found in the fronto parietal cortex of the urease treated hyperammonemic rat. Alterations in the metabolites of these compounds do not appear to be a major pathomechanism of ammonia toxicity in this brain area.

Ammonia↗

PubMed1995

Orthotopic liver transplantation for ornithine transcarbamylase deficiency with hyperammonemic encephalopathy.

Ornithine transcarbamylase (OTC) deficiency is an X chromosome-linked disorder causing hyperammonemic encephalopathy with a very poor prognosis. We describe here two patients with OTC deficiency, one a late on-set female patient (case 1) and the other a neonatal-onset male patient (case 2), who were successfully treated with orthotopic liver transplantation (OLTx). The OTC activity in the excised liver was 10% and 0% of control, respectively. Hyperammonemic encephalopathy was controlled with medical therapy in case 1 until the of 5 years, but the complicated course in case 2 in which hyperammonemia required peritoneal dialysis and hemodialysis in the neonatal period necessitated OLTx with a reduced-size liver at the age of 80 days. Both patients had restoration of serum ammonia level to normal in 2 and 3 days after liver replacement, and both patients have normal neurological and developmental status after 2 and 0.5 years of postoperative follow-up. These cases illustrate not only the metabolic cure of this disorder, but also the need to preserve neurological integrity by aggressive medical management of the hyperammonemia preoperatively and early surgical intervention when indicated, even if this is required very early in life.

Ammonia↗

PubMed1984

Methionine sulfoximine prevents the accumulation of large neutral amino acids in brain of hyperammonemic rats.

Accumulation of neutral amino acids in the brain due to altered transport across the blood-brain barrier appears to be a consequence of portal-systemic shunting and hyperammonemia. It has been suggested that high brain concentrations of glutamine, a product of cerebral ammonia detoxification, accelerates the transport of other neutral amino acids from blood to brain. To test this hypothesis, normal rats were infused with ammonium salts with or without pretreatment with L-methionine-dl-sulfoximine (MSO), an inhibitor of glutamine synthesis. Pretreatment with MSO prevented most ammonium salt-induced changes in the concentrations of the neutral amino acids in brain, suggesting that hyperammonemia alters the transport of neutral amino acids across the blood-brain barrier by causing the brain glutamine level to rise.

Amino Acids↗

PubMed1989

The physiologic basis of the TUR syndrome.

To better assess the role of hyperammonemia versus hypoosmolarity versus hyponatremia in the TUR syndrome, we developed a rat model. Sprague-Dawley female rats received an intraperitoneal injection (250 cc/kg body weight) of either 1.5% glycine, 2.0% glycine, 2.0% glycine plus 1.5% mannitol, 3.0% mannitol, 5.0% mannitol, or 2.0% glycine plus 0.25% saline. Arterial blood samples were obtained prior to injection, at 2, 8, 16, and 24 hr and analyzed for osmolarity, sodium, and ammonia. Those animals receiving 2.0% glycine, 2.0% glycine plus 1.5% mannitol, and 5.0% mannitol all died within 24 hr with lethargy, convulsions, and coma. Hyponatremia developed in all animals; death, however, occurred only when the sodium concentration declined to 90-95 meq/dl. Mannitol maintained serum osmolarity but did not prevent coma and death. Including 0.25% saline in the initial injection, or an iv injection of 5.0% saline delayed 8 hr achieved 100% survival. Ammonia concentrations increased 15-fold by 8 hr in groups receiving 2.0% glycine; it rapidly decreased to near normal by 24 hr. Decreasing the rise in ammonia by 50% with iv arginine had no effect on survival. Our results suggest that hyponatremia rather than hyperammonemia or hypoosmolarity accounts for the major morbidity and mortality secondary to the TUR syndrome.

Ammonia↗

PubMed1993

Effect of L-carnitine on cerebral and hepatic energy metabolites in congenitally hyperammonemic sparse-fur mice and its role during benzoate therapy.

Sparse-fur (spf) mutant mice with X-linked ornithine transcarbamylase deficiency were used to study the effect of L-carnitine on energy metabolites in congenital hyperammonemia. L-Carnitine was used at doses of 2, 4, 8, or 16 mmol/kg body weight (BW), and levels of ammonia, glutamine, glutamate, and some intermediates of energy metabolism were measured in brain and liver of spf/Y mice. Cerebral and hepatic levels of ammonia were decreased with 4 mmol L-carnitine (P < .001), whereas other doses did not seem to have any effect on this metabolite. Cerebral levels of glutamine were decreased following administration of L-carnitine at doses of up to 4 mmol/kg BW, whereas hepatic glutamine levels remained unaltered at all doses of L-carnitine. Both cerebral and hepatic levels of pyruvate, lactate, and alpha-ketoglutarate were decreased at doses of up to 8 mmol L-carnitine/kg BW. L-Carnitine treatment elevated adenosine triphosphate (ATP), free coenzyme A (CoA), and acetyl CoA levels in both brain and liver of spf/Y mice. Cytosolic and mitochondrial redox ratios of spf/Y mice, which were altered by congenital chronic hyperammonemia, were partially corrected by L-carnitine administration. L-Carnitine supplementation to spf/Y mice during sodium benzoate therapy also restored the availability of free CoA and ATP, thus counteracting the adverse effects of higher doses of sodium benzoate. These changes in free CoA and acetyl CoA levels could be due to the deinhibition of pantothenate kinase and stimulation of fatty acid oxidation by L-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1987

Blood ammonia levels and hepatic encephalopathy induced by CCl4 in rats.

An investigation of the mechanism of development of hepatic encephalopathy induced by CCl4 was performed in rats. CCl4 (1.0 ml/kg three times per week for over 10 weeks) caused hepatic encephalopathy in 80% of the treated rats. Accompanying the hepatic encephalopathy were hematemesis, abdominal dropsy, and hyperammonemia, conditions observed in hepatic coma patients. The blood ammonia levels were tremendously increased in only those rats with hepatic encephalopathy. Hepatic activities of carbamylphosphate synthetase (CPS) and argininosuccinate synthetase (ASS), important enzymes of the urea cycle, were significantly inhibited by CCl4. However, the causality between the inhibition of CPS or ASS activity and the increase in blood ammonia levels was not observed. On the other hand, the content of ATP, which is a substrate of CPS and ASS, was decreased by 60% in liver of rats with hepatic encephalopathy. The activity of Mg2+-ATPase which can decompose hepatic ATP was increased by 60 and 300% in mitochondria and microsomes, respectively, of livers of rats with CCl4-induced encephalopathy. There was a good correlation between the decreased hepatic ATP content and the increased mitochondrial Mg2+-ATPase activity. Furthermore, there was also a good correlation between the increase in blood ammonia levels and the increase in Mg2+-ATPase activity in microsomes. These findings suggest that hyperammonemia, which was produced by the decrease in hepatic content and by the inhibition of CPS and ASS, may play an important role in induction of hepatic encephalopathy.

Adenosine Triphosphate↗

PubMed1994

Activities of monoamine oxidase-A and -B are altered in the brains of congenitally hyperammonemic sparse-fur (spf) mice.

Activities of monoamine oxidases, MAOA and MAOB, were measured using radiometric assays in different brain regions of the sparse-fur (spf/Y) mouse, a model of congenital hyperammonemia resulting from an X-chromosomal defect of ornithine transcarbamylase. MAOA activities were decreased in cerebellum (by 23%, P < 0.05) and brainstem (by 16%, P < 0.05) of spf mice; activities of MAOB were concomitantly increased in cerebellum (by 22%, P < 0.05), brainstem (by 20%, P < 0.05) and cerebral cortex (by 22%, P < 0.05). These findings offer a rational explanation for previous findings of increased acidic metabolites of monoamines in the brain of spf mice. Altered monoaminergic function could be a key factor in the pathogenesis of neurological dysfunction in congenital hyperammonemias.

Ammonia↗

PubMed1995

Na+,K(+)-ATPase activities are increased in brain in both congenital and acquired hyperammonemic syndromes.

Activities of Na+,K(+)-ATPase were measured in brain regions of experimental animals with either congenital or acquired hyperammonemia. In the sparse-fur (spf) mutant mouse, with a genetic X-linked deficiency of ornithine transcarbamylase, an animal model of congenital hyperammonemia, Na+,K(+)-ATPase was increased in frontal cortex (by 57%, P < 0.001), cerebellum (by 61%, P < 0.001), brainstem (by 71%, P < 0.001) and striatum (by 48%, P < 0.01). Four weeks following portacaval anastomosis in the rat, Na+,K(+)-ATPase activities were increased in cerebellum and striatum (by 19%, P < 0.01) and in brainstem (by 28%, P < 0.01). Stimulation of Na+,K(+)-ATPase and the subsequent alteration of neuronal excitability could contribute to the CNS dysfunction characteristic of chronic hyperammonemic syndromes.

Ammonia↗

PubMed1986

Intestinal ammonia metabolism in ethanolic rats.

Repeated treatment of ethanol for 5 consecutive days has produced significant biochemical changes in the small intestine of the rat. The LDH and SDH were inhibited leading to deficient energy output from the glycolytic pathway and the Krebs cycle. The changes in ammonia metabolic profiles of intestine and blood indicate the presence of hyperammonemia. Enzymatic reactions associated with urea production and the levels of urea were increased. GS activity decreased explaining low levels of glutamine. These studies implicate PNC in producing hyperammonemia during ethanol treatment.

Ammonia↗

PubMed1987

Accumulation of large neutral amino acids in the brain of sparse-fur mice at hyperammonemic state.

Sparse-fur mice which are deficient in ornithine transcarbamylase, the second-step enzyme in the urea cycle, were examined for hyperammonemia and its relationship with encephalopathy. We compared amino acid concentrations in the serum and brain of spf mice with those of control mice. Unlike hepatic encephalopathy we could not find marked amino acid changes in the serum of spf mice besides low levels of citrulline and arginine. But in the brain of spf mice, glutamine was increased strikingly during hyperammonemia, and a concomitant accumulation of large neutral amino acids such as tyrosine, phenylalanine, methionine, and histidine was observed. The accumulation of these large neutral amino acids in the brain was not influenced by 24-hr fasting which caused increases in branched chain amino acids in the serum. From these results, we conclude that the accumulation of the large neutral amino acid in the brain of hyperammonemic state is caused by uptake of ammonia in the brain and the subsequent accumulation of glutamine, but is not influenced by a decreased ratio of branched chain amino acids to aromatic amino acids in the serum.

Aging↗

PubMed1989

Serotonin- and catecholamine-related substances in the brain of ornithine transcarbamylase-deficient Sparse-fur mice in the hyperammonemic state: comparison of two procedures for obtaining brain extract, decapitation and microwave irradiation.

Increased flux through the 5-HT pathway during hyperammonemia was indicated by a significant positive correlation between Gln concentration and the ratio of 5-HIAA to 5-HT in the brain of spf mice taken after microwave irradiation to prevent postmortem changes in metabolites. There were no significant changes in the catecholamine pathway in the brain during hyperammonemia despite the increases in Try and Phe.

Ammonia↗

PubMed2005

Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier.

Citrin, encoded by SLC25A13, is a liver-type mitochondrial aspartate-glutamate carrier (AGC), of which deficiency, in autosomal recessive trait, causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). NICCD patients have jaundice, hypoproteinemia, hypoglycemia, galactosemia, growth retardation, fatty liver and multiple aminoacidemia including citrulline, methionine, threonine and tyrosine. Some of the neonates who have experienced NICCD suffer from severe CTLN2 more than 10 years or several decades later. In CTLN2, neuropsychotic symptoms such as disorientation, aberrant behavior, coma and death are observed. Laboratory findings reveal hyperammonemia, citrullinemia, fatty liver and liver-specific decrease in a urea cycle enzyme, argininosuccinate synthetase (ASS). In some cases, hyperlipidemia, pancreatitis and hepatoma are accompanied with CTLN2. Citrin as a liver-type AGC plays a role in supplying aspartate to the cytosol for urea, protein and nucleotide synthesis by exchanging mitochondrial aspartate for cytosolic glutamate and proton, and transporting cytosolic NADH reducing equivalent to mitochondria as a member of malate aspartate shuttle essential for aerobic glycolysis. AGC is also important for gluconeogenesis from lactate. Although it is difficult to explain pathogenesis of the symptoms such as cholestasis in NICCD and liver-specific decrease of ASS protein in CTLN2 from the functions of the AGC, some are understandable by the loss of citrin functions. Many CTLN2 patients have been treated with a low protein and high carbohydrate diet and glycerol at the hyperammonemic coma. We argue that those treatments may result in fatty liver, hyperlipidemia, hyperammonemia and even death due to loss of the citrin functions. Loss of citrin first cause deficiency of aspartate in the cytosol, which results in an increase in cytosolic NADH/NAD(+) ratio and then activation of fatty acid synthesis pathway to compensate the aberrant ratio. This follows inhibition of fatty acid oxidation. The peculiar fondness for food of CTLN2 patients who like protein and dislike carbohydrate and sweets may be related to their metabolic requirements.

Journal Article↗

PubMedDate not supplied

Neurons exposed to ammonia reproduce the differential alteration in nitric oxide modulation of guanylate cyclase in the cerebellum and cortex of patients with liver cirrhosis.

The activation of soluble guanylate cyclase by nitric oxide is increased in the frontal cortex but is reduced in the cerebellum of patients who died with liver cirrhosis. The aims of this work were to assess whether hyperammonemia is responsible for the region-selective alterations in guanylate cyclase modulation in liver cirrhosis and to assess whether the alteration occurs in neurons or in astrocytes. The activation of guanylate cyclase by nitric oxide was lower in cerebellar neurons exposed to ammonia (1.5-fold) than in control neurons (3.3-fold). The activation of guanylate cyclase by nitric oxide was higher in cortical neurons exposed to ammonia (8.7-fold) than in control neurons (5.5-fold). The activation was not affected in cerebellar or cortical astrocytes. These findings indicate that hyperammonemia is responsible for the differential alterations in the modulation of soluble guanylate cyclase in cerebellum and cerebral cortex of cirrhotic patients. Moreover, the alterations occur specifically in neurons and not in astrocytes.

Ammonia↗

PubMed2005

Effects of acute ammonia toxicity on nitric oxide (NO), citrulline-NO cycle enzymes, arginase and related metabolites in different regions of rat brain.

Nitric oxide (NO) is involved in many pathophysiological processes in the brain. NO is synthesized from arginine by nitric oxide synthase (NOS) enzymes. Citrulline formed as a by-product of the NOS reaction, can be recycled to arginine by successive actions of argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) via the citrulline-NO cycle. Hyperammonemia is known to cause poorly understood perturbations of the citrulline-NO cycle. To understand the role of citrulline-NO cycle in hyperammonemia, NOS, ASS, ASL and arginase activities, as well as nitrate/nitrite (NOx), arginine, ornithine, citrulline, glutamine, glutamate and GABA were estimated in cerebral cortex (CC), cerebellum (CB) and brain stem (BS) of rats subjected to acute ammonia toxicity. NOx concentration and NOS activity were found to increase in all the regions of brain in acute ammonia toxicity. The activities of ASS and ASL showed an increasing trend whereas the arginase was not changed. The results of this study clearly demonstrated the increased formation of NO, suggesting the involvement of NO in the pathophysiology of acute ammonia toxicity. The increased activities of ASS and ASL suggest the increased and effective recycling of citrulline to arginine in acute ammonia toxicity, making NO production more effective and contributing to its toxic effects.

Amino Acids↗

PubMed2000

Carnitine-acylcarnitine translocase deficiency: metabolic consequences of an impaired mitochondrial carnitine cycle.

We describe a patient with carnitine-acylcarnitine translocase deficiency (MIM 212138), who presented with neonatal generalized seizures, heart failure, and coma. Laboratory evaluation revealed hypoglycemia, hyperammonemia, lactic acidemia, hyperuricemia, and mild dicarboxylic aciduria. The fact that total plasma carnitine (7.1 micromol/l [20-30]) and free carnitine (1.9 micromol/l [12-18]) were low together with a high acylcarnitine/free carnitine ratio of 2.7 [0.4-1.0] prompted acylcarnitine analysis. This revealed the presence of large amounts of long-chain derivatives including C(16:0), C(16:1), C(18:1), C(18:2). Based on these findings carnitine-acylcarnitine translocase deficiency was suspected which was confirmed by enzyme studies in fibroblasts. The underlying complex metabolic consequences of this defect are reviewed. Prenatal diagnosis was performed in a subsequent pregnancy and a defect ruled out by measurement of carnitine-acylcarnitine translocase activity in cultured chorionic villi cells. As the clinical recognition of a life-threatening fatty acid oxidation disorder may be difficult, defects in this pathway should be considered in any child with coma, an episode of a Reye-like syndrome, and cardiomyopathy. Since routine laboratory tests often do not provide clues about potential disorders and profiles of urinary organic acids may not be characteristic, we recommend to measure free carnitine and acylcarnitines in plasma in any child with hyperammonemia, hypo/hyperketotic hypoglycemia or lactic acidemia for prompt treatment, proper genetic counseling, and potential prenatal diagnosis.

Ammonia↗

PubMed2003

Ammonia potentiates methylmalonic acid-induced convulsions and TBARS production.

Hyperammonemia is a common finding in children with methylmalonic acidemia, an inherited metabolic disease characterized by mental retardation, convulsions, and accumulation of methylmalonic acid (MMA). Although it has been suggested that MMA induces convulsions through succinate dehydrogenase (SDH) inhibition, very little is known about the contribution of hyperammonemia to the development of convulsions in these patients. In the present study we investigated the effects of ammonium ions on the convulsant action of MMA, MMA-induced inhibition of striatal succinate dehydrogenase, and the striatal content of thiobarbituric acid-reactive substances (TBARS). Adult rats were injected with ammonium acetate (1.5 mmol/kg, sc) or sodium acetate (1.5 mmol/kg, sc), followed 5 min later by buffered MMA (3 micromol/microl) or NaCl (4.5 micromol/microl) injected into the striatum. The animals were observed in an open field for the appearance of convulsive episodes. After 30 min of behavioral evaluation, the animals were sacrificed and had their striatal TBARS content measured. Ammonium acetate pretreatment caused no behavioral effects per se, but potentiated MMA-induced convulsions and increased basal TBARS content and MMA-induced TBARS production in the striatum. Ammonium chloride had no effect on basal succinate dehydrogenase activity and did not alter MMA-induced inhibition of SDH in vitro. These results suggest that ammonia potentiates MMA-induced behavioral effects through a mechanism that does not involve further succinate dehydrogenase inhibition, but may involve facilitation of MMA-induced oxidative damage and provide evidence that ammonia and MMA may have mutually additive toxicity.

Acetates↗

PubMed1998

Treatment of ornithine transcarbamylase deficiency in girls by auxiliary liver transplantation: conceptual changes in a living-donor program.

BACKGROUND/PURPOSE: Ornithine transcarbamylase (OTC) deficiency is an X-chromosome-linked genetic disorder resulting in hyperammonemia hepatic dysfunction, coma, and serious neurological sequelae. This report describes an experience in treating this condition with living-related liver transplantation. METHODS: Three children with OTC were treated with a living-related liver transplantation. Potential donors were evaluated with the allopurinol loading test to exclude heterozygotes. FK506 and low-dose steroids were used for immunosuppression. Auxiliary partial orthotopic transplantation (APOLT) was used in two of the cases. RESULTS: All three children survived and are doing well without protein restriction. CONCLUSIONS: These observations suggest that in OTC removal of the native liver is not necessary because (1) a partial liver segment with normal enzyme activity corrects the hyperammonemia, (2) in case of graft failure the native liver is an available backup, and (3) the native liver has the ability to recover function. As long as living-related donors serve as the main source of donor organs, APOLT is a safer approach to liver transplantation in OTC.

Amino Acid Metabolism, Inborn Errors↗

PubMed1999

Successful coil embolization in an infant with congenital intrahepatic portosystemic shunts.

The authors report the case of a 7-month-old Japanese infant with congenital intrahepatic portosystemic shunts. He had hypergalactosaemia and hyperammonemia at age 1 month. The diagnosis was made by ultrasonography and angiography. Coil embolization was performed successfully, and then hyperammonemia and hypergalactosaemia improved soon after surgery.

Embolization, Therapeutic↗