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PubMed1993

Region-selective reductions in activities of glutamine synthetase in rat brain following portacaval anastomosis.

Portacaval anastomosis in the rat results in liver atrophy, sustained hyperammonemia and mild encephalopathy. Previous studies have demonstrated region-selective alterations of glutamine and other ammonia-related amino acids in brain following portacaval anastomosis. Ammonia removal by brain relies on glutamine synthesis and the enzyme responsible, glutamine synthetase, has an almost exclusively astrocytic localization. Glutamine synthetase activities were measured using a radioenzymatic assay in homogenates of seven brain regions of rats four weeks after end-to-side portacaval anastomosis. Enzyme activities were significantly reduced in hippocampus (by 25%, p < 0.01), in cerebellum (by 29%, p < 0.01) and in cerebral cortex (by 14%, p < 0.05). Enzyme activities in other brain regions were within normal limits. Region-selective reductions of glutamine synthetase following portacaval anastomosis could result in disruption of neuron-glial metabolic interactions and in a deficit of glutamatergic synaptic regulation. Similar mechanisms could be implicated in the pathogenesis of hepatic encephalopathy accompanying chronic liver disease in humans.

Ammonia↗

PubMed1993

Astrocytes and the entry of circulating ammonia into the brain: effect of fluoroacetate.

Chronic hyperammonemia is known to lead to pathological forms of astrocytes. To test the influence of these changes on the neurotoxicity of ammonia, the glial metabolic poison fluoroacetate (FA) was applied locally, through microdialysis to the hippocampal dentate gyrus. The penetration of ammonia into the brain following the i.p. injection of 7.8 mmol/kg NH4 acetate was evaluated by measuring the ammonia and glutamine content of the microdialysate. Field EPSPs (fEPSPs) evoked by perforant path stimulation were recorded 1.5 mm from the microdialysis probe. When 20 mM FA was perfused, NH4 acetate injection increased the ammonia efflux by 300% and decreased fEPSPs by 40%, but glutamine concentration remained low. With no FA in the microdialysate, NH4 acetate treatment increased the efflux of ammonia by only 60%, did not affect fEPSPs but doubled glutamine efflux. Arterial ammonia content, as measured by microdialysis in the common carotid, increased 4-5 fold following i.p. administration of NH4 acetate, while arterial glutamine was not elevated. Systemically administered FA did not affect either of these changes significantly, but slightly reduced arterial pH. These observations indicate that FA applied by microdialysis acted locally on astrocytes and therefore impaired astrocytic function contributes to the development of hepatic encephalopathy by facilitating the entry of ammonia into the brain. Inhibition of excitatory synaptic transmission by elevated brain ammonia may underlay CNS depression in hepatic encephalopathy.

Ammonia↗

PubMed1986

Cerebral aminoacids in portal-systemic encephalopathy: lack of evidence for altered gamma-aminobutyric acid (GABA) function.

Construction of an end-to-side portocaval anastomosis in the rat resulted, 4 weeks later, in sustained hyperammonemia and two- to threefold increases in brain ammonia. Measurement of cerebral amino acids using a sensitive double-isotope dansyl microtechnique revealed substantial increases in the glutamine content of cerebral cortex and brain stem. Glutamate levels were found to be concomitantly reduced in both brain regions compared to those of sham-operated controls. The gamma-aminobutyric acid (GABA) content of cerebral cortex and brain stem was unaffected by portocaval shunting, as were activities of the GABA nerve-terminal marker enzyme glutamic acid decarboxylase (GAD). These findings suggest that impaired GABA function may not play a major role in the pathogenesis of hepatic encephalopathy associated with portocaval shunts. Preliminary evidence suggests that decreased cerebral glutamate may reflect its loss from the releasable (neurotransmitter) pool.

Amino Acids↗

PubMed1982

Ammonia-induced changes in pancreatic hormones and plasma amino acids in patients with liver cirrhosis.

The contribution of hyperammonemia to plasma amino acid imbalance in patients with liver disease was assessed in 10 subjects with chronic hepatitis and in 17 advanced cirrhotics. Insulin, glucagon, and plasma amino acids were determined both in the basal state and 45 min after oral ammonium chloride, at doses used in the ammonia-tolerance test. In cirrhotics, ammonia increased to 3 times basal values, in association with a rise in insulin and, more marked, in glucagon. Aromatic amino acids and free tryptophan further increased, while a significant fall in branched-chain amino acids and glutamate was observed. The increase in ammonia levels strongly correlated with the increase in glucagon (r = 0.707). Two patients, with large esophageal varices, showed signs of disturbed consciousness, in association with a marked rise in ammonia and in the ration of free tryptophan to the sum of neutral amino acids. In patients with chronic hepatitis, whose ammonia levels rose slightly, minor variations in pancreatic glucoregulatory hormones and plasma amino acids were observed, as also happened in 10 healthy subjects following ammonium chloride ingestion. Our data fit with the hypothesis that the plasma amino acid imbalance of cirrhotics may be partly due to ammonia-induced changes in pancreatic hormones.

Adult↗

PubMed1992

Effect of portacaval anastomosis on glutamine synthetase activities in liver, brain, and skeletal muscle.

Glutamine synthetase is responsible for the ATP-dependent amidation of glutamate to glutamine. In liver the enzyme is highly localized in perivenous hepatocytes; in brain the enzyme is localized in astrocytes. Portacaval anastomosis resulted in liver atrophy, hyperammonemia, and up to 90% loss of glutamine synthetase activity in liver homogenates. This effect, which appears to be irreversible, probably reflects the selective loss of perivenous hepatocytes following portacaval anastomosis. Glutamine synthetase activities in brain were unaffected by portacaval anastomosis of up to 12 weeks' duration. Enzyme activities in homogenates of skeletal muscle, on the other hand, were significantly increased at one and four weeks after shunt surgery. These effects were not the result of decreased food intake in shunted animals. These findings suggest fundamentally different regulatory mechanisms for glutamine synthetase in these tissues. Skeletal muscle may thus provide an important alternative site for ammonia detoxification after portal-systemic shunting.

Ammonia↗

PubMed1993

[Repeated perioperative administration of fructose and sorbitol in a female patient with hereditary fructose intolerance [HFI)].

The present paper reports on an adult female patient whose hereditary fructose intolerance (HFI) was at first not diagnosed and who, within the space of 2 years after repeated elective surgery and the perioperative administration of fructose and sorbitol, developed "hepatic and renal failure of unclear origin." At a later stage we were able to establish the diagnosis of HFI by means of a fructose tolerance test in both she and her brother, for whom intolerance to fruit and desserts had been known since early childhood. In addition, literature references to fatalities following the parenteral application of fructose and sorbitol were analyzed. During the course of fructose infusion in both the patient and her brother with HFI, the following metabolic changes were noted: hypoglycemia, elevated rise in the blood fructose concentration, hyperlactacidemia, elevated rise in the blood fructose concentration, hyperlactacidemia, and hyperammonemia. These metabolic changes proved to be reversible after discontinuing the fructose infusion. Analysis of the literature on the fatalities following parenteral fructose administration established that fruit and dessert intolerance was known for all collated patients with HFI, and that, clearly, no regular metabolic tests had been conducted.

Acute Kidney Injury↗

PubMedDate not supplied

Current concepts in inguinal hernia in infants and children.

Trends are changing in the management of infants and children with indirect inguinal hernias. Advances in neonatal intensive care have resulted in the survival of many small premature infants who have a high incidence of inguinal hernia. The rate of incarceration, strangulation, and gonadal infarction in these babies is twice that of the general pediatric age group. Respiratory immaturity, apnea, bradycardia, and associated neonatal conditions require special management at the time of hernia repair, usually performed just before discharge from the neonatal intensive care unit. New information concerning volume loss and depletion of germ cells beginning at 6 months of age in boys with undescended testes has stimulated the performance of orchiopexy when the patient is 1 year of age. More than 90% of boys with cryptorchid testes at the age of 1 year have an associated hernia that requires concomitant repair at the time of orchiopexy. The use of the peritoneal cavity for fluid absorptive purposes in hydrocephalus treated by venticuloperitoneal shunts or of peritoneal dialysis for renal failure and metabolic diseases such as hyperammonemia and lactic acidosis causes increased intraabdominal pressure and results in the appearance of a previously unrecognized hernia. Recognition of these and other conditions associated with a high incidence of hernial occurrence should allow early diagnosis and treatment before the development of complications. Most elective repairs of hernias are safely performed in the outpatient setting; however, some infants and children with concurrent illnesses are best managed in a "morning admissions" program, in which hospital admission occurs postoperatively.

Child↗

PubMed1990

Organization of hepatic nitrogen metabolism and its relation to acid-base homeostasis.

Hepatic and renal nitrogen metabolism are linked by an interorgan glutamine flux, coupling both renal ammoniagenesis and hepatic ureogenesis to systemic acid base regulation. This is because protein breakdown produces equimolar amounts of NH4+ and HCO3-. A hepatic role in this interorgan team effort is based upon the tissue-specific presence of urea synthesis, which represents a major irreversible pathway for removal of metabolically generated bicarbonate. A sensitive and complex control of bicarbonate disposal via ureogenesis by the extracellular acid-base status creates a feed-back control loop between the acid-base status and the rate of bicarbonate elimination. This bicarbonate-homeostatic mechanism operates without threat of hyperammonemia, because a sophisticated structural and functional organisation of ammonia-metabolizing pathways in the liver acinus uncouples urea synthesis from the vital need to eliminate potentially toxic ammonia.

Acid-Base Equilibrium↗

PubMed1989

The effect of ammonia infusion on brain monoamine metabolism in portacaval-shunted rats.

The effect of ammonia infusion on monoamine metabolism was studied in the rat brain. Seven days after portocaval shunt (PCS) or sham operation animals were infused with ammonia or saline. Brain metabolism of serotonin and norepinephrine was studied after injection of a decarboxylase inhibitor (m-hydroxybenzylhydrazine, NSD 1015) which blocks the conversion of 5-hydroxytryptophan to serotonin and dihydroxyphenylalanine to dopamine. Neurologic testing was conducted before killing. Plasma and brain amino acids were measured. PCS animals infused with ammonia were in deep coma after 6 h infusion, whereas sham-operated animals were virtually unaffected. Brain amino acid analyses demonstrated increased concentrations of the aromatic amino acids and a tenfold increase in glutamine. Serotonin metabolism was diminished after 6 h. Dopamine synthesis was normal, but norepinephrine levels were low after 6h. The study suggests that hyperammonemia in PCS rats results in a depression of the serotonin synthesis rate in accordance with two previous studies but in contrast to previous hypotheses on the regulation of serotonin metabolism.

5-Hydroxytryptophan↗

PubMed1985

Excitatory and inhibitory amino acid neurotransmitters and ammonia metabolism in hepatic failure rats.

The molar ratio of excitatory amino acid neurotransmitters (glutamate and aspartate) to inhibitory amino acid neurotransmitters (r-aminobutyric acid, GABA, and glycine) in the brain was diminished in acute hepatic failure rats with hyperammonemia, brain edema, and abnormal electroencephalograms. The ratio was further decreased with a marked elevation of arterial and brain ammonia levels 30 min after ammonium acetate was administered i.p. to hepatic failure rats. A continuous infusion of a branched chain amino acid (BCAA) solution before and after the ammonia loading effectively reversed the ammonia-induced lowering of this ratio; high ammonia contents in the brain were concomitantly decreased. Infusing glutamate instead of the BCAA solution failed to produce similar effects probably because of limited entry of glutamate into the brain. The above results suggest that excitatory and inhibitory amino acid neurotransmitter (glutamate, aspartate, and GABA) levels in the brain of hepatic failure rats might vary with abnormal cerebral ammonia metabolism.

Ammonia↗

PubMed1986

Arterial ammonemia changes of renal origin induced in the rat by acid and alkaline diets.

The aim of this study was to investigate the influence of acid and alkali food supplementation on systemic ammonemia to explain the hyperammonemia previously observed in rats fed a high protein diet. In normal rats, arterial ammonia concentration significantly increases after 4 days of HCl-supplemented diet. Following a NaHCO3-enriched food, there is only a slight but not significant decrease in arterial ammonia level. These changes occur before any variation in arterial acid-base status and are of renal origin. Indeed, there is a positive linear correlation (r = 0.946; P less than 0.001) between arterial ammonia level and the ammonia concentration difference between the renal vein and artery (which varies proportionally to the urinary ammonium excretion). Hindquarter uptake and intestinal release of ammonia do not significantly participate in the arterial ammonia changes observed. Following HCl-enriched diets, increased renal glutamine uptake, enhanced hindquarter glutamine release, and perhaps decreased intestinal glutamine uptake occur simultaneously. In conclusion, acid and alkali food supplementation intervenes on the renal ammonia release into the circulation with concomitant arterial ammonemia changes.

Ammonia↗

PubMed1982

Activity of orotate metabolizing enzyme complex and various urea-cycle enzymes in mutant mice with ornithine transcarbamylase deficiency.

The overall activity of the enzyme complex consisting of orotate phosphoribosyl transferase and orotidine monophosphate decarboxylase, and of various enzymes of the urea cycle, has ben studied in sparse-fur (spf) mutant mice with ornithine transcarbamylase deficiency. The enzyme complex has a lower overall activity, which could be caused by disturbed pyrimidine metabolism due to hyperammonemia. Other enzymes of the urea cycle do not show any significant change.

Animals↗

PubMed1994

Effects of ornithine aminotransferase inactivation by 5-fluoromethylornithine in rats following portacaval anastomosis.

5-Fluoromethylornithine (5FMOrn) is a selective inactivator of ornithine aminotransferase. Administration of this compound to rodents causes a prominent increase of tissue ornithine concentrations, and prevents the neurological consequences of acute ammonia intoxication. However, long-term treatment with 5FMOrn of rats with portacaval shunts did not result in decreased circulating ammonia concentrations, nor did it prevent other pathologic manifestations of shunting. The sensitivity to ammonia intoxication of rats with portacaval shunts was also unaffected by pretreatment with 5FMOrn, although liver ornithine concentrations were significantly elevated; specific activities of urea cycle enzymes were slightly higher in portacaval shunted compared to sham-operated controls following 5-FMOrn treatment. Administration of 5FMOrn dramatically elevated urinary excretion of several amino acids in rats with portacaval shunts, but not in sham-operated animals, suggesting that the reabsorption of amino acids from the glomerular filtrate may be impaired in shunted rats. These results suggest that, in contrast to acute hyperammonemic syndromes, 5-FMOrn may be of limited therapeutic value in chronic hyperammonemia syndromes in which there is significant portal-systemic shunting.

Amino Acids↗

PubMed1994

Regional amino acid neurotransmitter changes in brains of spf/Y mice with congenital ornithine transcarbamylase deficiency.

Congenital deficiencies of the urea cycle enzyme ornithine transcarbamylase (OTC) result in chronic hyperammonemia and severe neurological dysfunction including seizures and mental retardation. As part of a series of studies to elucidate the pathophysiologic mechanisms responsible for the CNS consequences of OTC deficiency, concentrations of ammonia-related and neurotransmitter amino acids were measured as their o-phthalaldehyde derivatives using high performance liquid chromatography with fluorescence detection in regions of the brains of sparse-fur (spf) mice, a mutant with an X-linked inherited defect of OTC. Compared to CD-1/Y controls, the brains of spf/Y mutant mice contained significant alterations of several amino acids. A generalized, up to 2-fold, increase of brain glutamine was observed, consistent with the exposure of these brains to increased concentrations of ammonia. Significant increases of brain alanine were also observed and, together with previous reports of increased concentrations of alpha-ketoglutarate, are consistent with ammonia-induced inhibition of alpha-ketoglutarate dehydrogenase in the brains of spf/Y mice. Increased brain content of the excitatory amino acid aspartate could be responsible for the seizures frequently encountered in congenital OTC deficiency.

Amino Acid Metabolism, Inborn Errors↗

PubMed1991

Urea cycle defect: a case with MR and CT findings resembling infarct.

A 2 1/2 year old girl was admitted to the hospital because of recurrent vomitting, impaired consciousness, and hyperammonemia. MR and CT findings resembled an infarct, but she was found to have a defect in the urea cycle, partial ornithine transcarbamylase deficiency.

Amino Acid Metabolism, Inborn Errors↗

PubMed1978

Protein load in argininosuccinic aciduria: thoughts on its biochemical implications.

A patient with argininosuccinc aciduria was charged with 50 grams of protein, which was followed by considerable hyperammonemia. There was no response in further urea formation; but there was a considerable production of orotic acid, a precursor of pyrimidines. This makes orotic acid to an important diagnostic tool for the diagnosis of impaired urea formation. The patient's plasma amino acid pattern led to the suggestion that orotic acid synthesis is initiated by increased de novo formation of carbamyl phosphate in the cytosol and not by deviation of already existing intramitochondrial carbamyl phosphate.

Adult↗

PubMed1996

Flumazenil does not affect the increase in rat hippocampal extracellular glutamate concentration produced during thioacetamide-induced hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric disorder that often occurs as a consequence of acute or chronic liver failure. Previous reports have suggested that alterations in amino acid neurotransmission, particularly glutamate, may play an important role in the pathogenesis of HE. The objectives of the present study were to test the hypothesis that extracellular glutamate concentration is increased during HE, and to determine if flumazenil, a benzodiazepine antagonist, alters the extracellular concentration of glutamate during HE. The experimental approach involved using microdialysis probes to measure rat hippocampal extracellular glutamate concentration. HE was brought about as a result of thioacetamide-induced liver failure. Thioacetamide produced behavioral and metabolic effects, such as somnolence, hyperventilation and hyperammonemia, consistent with stage three HE. Comparison with saline-treated rats demonstrated that HE was associated with a significant increase (p = 0.010) in extracellular hippocampal glutamate concentration. Administration of flumazenil caused a transient increase in arousal level, but did not affect the increase in glutamate concentration (p = 0.93). These results corroborate the theory that glutamate neurotransmission is altered during HE and suggest that the flumazenil arousal of HE rats is not mediated by a change in extracellular glutamate concentration.

Animals↗

PubMed1987

Acute hepatic failure after open-heart surgery in children.

Acute hepatic failure (AHF) combined with acute renal failure (ARF) is a well-known complication of open-heart surgery in adults. The occurrence of this complication in two children after open-heart surgery for correction of congenital heart disease is reported. Hypotension occurred during the operation and was treated by catecholamine vasopressors. AHF set in during the postoperative course; it was manifested by impaired consciousness, hypoglycemia, hyperbilirubinemia, hyperammonemia, elevated liver enzymes and prolongation of the prothrombin time with failure of hemostasis. ARF also developed in both children. One of the patients survived the acute episode of hepatic failure. The importance of early diagnosis, routine close monitoring, and appropriate selection of vasopressors is emphasized.

Acute Disease↗