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PubMed1984

[Hyperammonemia and decrease of growth and nocturnal locomotion in rats with portal stricture and uremia].

In order to make clearer the pathogenesis of hepatic coma, the clinical tolerance of progressive levels of chronic hyperammonemia were studied in the rat. Increases of blood ammonia in the range of 200 to 600 micrograms/dl were produced within 4 weeks by stricture of the portal vein associated with progressive rises in blood urea resulting from reduction of the renal mass and/or addition of urea to the food. The portal stricture produces a collateral circulation allowing a hepatic bypass of portal blood and the ammonia level of this blood is proportional to the amount of circulating and alimentary urea hydrolyzed in the digestive tract. Only the highest hyperammonemias were associated with decreased nocturnal locomotion of the rats and decrease in the growth rate. The latter was correlated with the ammonia levels. No animal presented signs of coma. These results suggest a good cerebral tolerance by the rat of important chronic hyperammonemias which however seem to have an anorexic effect.

Ammonia↗
PubMed1994

Inherited metabolic disorders in Pakistan: presentation, diagnosis and outcome of congenital hyperammonemias.

A total of 21 patients were admitted to Aga Khan University Hospital with suspected congenital hyperammonemias during the period 1989 to 1992. There were 11 patients with acidosis and 10 patients were without acidosis. Prominent clinical manifestations included positive family history (76%), onset in the first week of life (67%) and neurological manifestations (76%). Of patients with hyperammonemia and acidosis, 4 had severe metabolic acidosis with anion gap of 30mEq/L and above. Of patients with hyperammonemia without acidosis, 4 had ammonia level ranging from 1600-2000 mg/dl. Diagnosis was confirmed in only 1 patient and that was also done abroad. Overall mortality was 71%. In conclusion, these disorders are not uncommon in our country and should be suspected in all infants with above clinical or biochemical abnormalities.

Ammonia↗
PubMed1993

Diagnosis and outcome of congenital hyperammonemias.

A total of 21 patients were admitted to Aga Khan University Hospital with suspected congenital hyperammonemias during the period 1989 to 1992, 11 with acidosis and 10 without acidosis. Prominent clinical manifestations included positive family history (76%), onset in the first week of life (67%) and neurological manifestations (76%). Of patients with hyperammonemia and acidosis, 4 had severe metabolic acidosis with anion gap of 30mEq/L and above. Of patients with hyperammonemia without acidosis, 4 had ammonia level ranging from 1600-2000 micrograms/dl. Diagnosis was confirmed in only 1 patient and that was also done abroad. Overall mortality was 71%. These disorders are not uncommon in our country and should be suspected in all infants with above clinical or biochemical abnormalities.

Acidosis↗
PubMed1998

[Inherited hyperammonemia].

Inherited hyperammonemia disorders are caused by specific enzymatic defects in the urea cycle or in metabolic pathways related to it. These disorders can be divided into the following groups: deficiencies of urea cycle enzymes, transport defects of dibasic amino acids, organic acidemias, defects in beta-oxidation of fatty acids, transient hyperammonemia of the newborn-probably a not genetically determined disorder. Manifestation of the mentioned disorders includes elevated serum ammonia level resulting in altered level of consciousness and/or persisted vomiting. Occurrence of irreversible neurologic sequelae depends mostly on the extent of hyperammonemic period. Differential diagnosis includes blood gas, anion gap, plasma amino acids analysis and urine organic acids analysis. In some cases specific tissue enzymes activity measurement is necessary. Dialysis, sodium benzoate, sodium phenylacetate and arginine are used in the treatment of acute hyperammonemia. In addition oral or rectal neomycin and/or lactulose can be used, which reduces intestinal ammonia production.

Amino Acid Metabolism, Inborn Errors↗
PubMed2000

Antagonizing effect of AP-1 on glucocorticoid induction of urea cycle enzymes: a study of hyperammonemia in carnitine-deficient, juvenile visceral steatosis mice.

Hyperammonemia is one of the major symptoms of primary carnitine deficiency. Carnitine-deficient juvenile visceral steatosis (JVS) mice show hyperammonemia during the weaning period. We have found that all of the urea cycle enzyme genes are suppressed and that N-acetylglutamate, an allosteric activator of the first step enzyme of the urea cycle, carbamoyl phosphate synthetase I (CPS), is not deficient in the liver of JVS mice. Induction of the urea cycle enzymes by glucocorticoid in rat primary cultured hepatocytes was suppressed by the addition of long-chain fatty acids. The suppression of the urea cycle enzyme genes in vivo and in vitro is accompanied by stimulated AP-1 DNA-binding activity. However, mRNA of phosphoenolpyruvate carboxykinase, one of the gluconeogenic enzymes which responds to glucocorticoid, is further stimulated by the addition of fatty acid. From these results, we postulate that protein-protein interaction between glucocorticoid receptors and AP-1 is not the major mechanism of suppression, but that AP-1 causes the suppression through a cis-element on the gene. After cloning promoter and enhancer regions of the mouse CPS gene and comparing rat and mouse, we found that an AP-1 site was present just 3'-downstream of the minimal essential enhancer fragment previously described. We also found that the presence of an AP-1 site in reporter gene constructs resulted in suppression of the reporter genes in the liver of carnitine-deficient JVS mice and suppression of glucocorticoid induction by long-chain fatty acid in cultured hepatocytes.

Animals↗
PubMed2003

Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia.

N-acetylglutamate synthase (NAGS) is a mitochondrial enzyme that catalyzes the formation of N-acetylglutamate, an essential allosteric activator of carbamyl phosphate synthetase I, the first enzyme of the urea cycle. Liver NAGS deficiency has previously been found in a small number of patients with hyperammonemia. The mouse and human NAGS genes have recently been cloned and expressed in our laboratory. We searched for mutations in the NAGS gene of two families with presumed NAGS deficiency. The exons and exon/intron boundaries of the NAGS gene were sequenced from genomic DNA obtained from the parents of an infant from the Faroe Islands who died in the neonatal period and from two Hispanic sisters who presented with acute neonatal hyperammonemia. Both parents of the first patient were found to be heterozygous for a null mutation in exon 4 (TGG-->TAG, Trp324Ter). Both sisters from the second family were homozygous for a single base deletion in exon 4 (1025delG) causing a frameshift and premature termination of translation. The finding of deleterious mutations in the NAGS gene confirms the genetic origin of NAGS deficiency. This disorder can now be diagnosed by DNA testing allowing for carrier detection and prenatal diagnosis.

Acetyltransferases↗
PubMed2001

Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome.

The hyperinsulinism-hyperammonemia syndrome (HHS) has been shown to result from 'gain-of-function' mutations of the glutamate dehydrogenase (GlDH) gene, GLUD1. In the original report, all mutations were found in a narrow range of 27 base pairs within exons 11 and 12 which predicted an effect on the presumed allosteric domain of the enzyme and all these mutations were associated by a diminished inhibitory effect of guanosine triphosphate (GTP) on GlDH activity. We have investigated 14 patients from seven European families with mild hyperinsulinism. In four families, more than one member was affected. In eight cases hyperammonemia was documented, and eight cases had signs of significant leucine sensitivity. In one of the families, a novel heterozygous missense mutation in exon 6 [c.833C>T (R221C)] was detected, and in all other cases from six unrelated families the novel heterozygous missense mutation c.978G>A (R269H) was found in exon 7. When GIDH activity was measured in lymphocytes isolated from affected patients, both mutations were shown to result in a normal basal activity but a diminished sensitivity to GTP. It is the first time that this effect is reported for mutations located in the presumed catalytic site and outside the GTP allosteric domain of the enzyme. The observation of the high prevalence of the exon 7 mutation both in familial and sporadic cases of HHS suggests a mutation hot spot and justifies a mutation screening for this novel mutation by mismatch PCR-based restriction enzyme digestion in patients with hyperinsulinism.

Adolescent↗
PubMed2004

Antioxidant defence of the neonatal rat brain against acute hyperammonemia.

Oxidative stress associated with the presence of elevated concentrations of ammonia in the brain has been proposed as one possible mechanism involved in ammonia toxicity. In a previous study [Brain Res.973 (2003) 31], we reported that neonatal rats are more resistant to acute ammonia toxicity than adult rats. In the present work, we studied the antioxidant status of the brain in hyperammonemic neonatal rats. Increased activities of the antioxidant enzymes and enhanced glutathione content were found in the brains of the hyperammonemic neonatal rats as compared to the controls. In addition, no changes in brain reactive oxygen species (ROS) levels and lipid peroxidation due to hyperammonemia were found. Therefore, acute ammonia intoxication does not induce oxidative stress in neonatal rats, a fact that may explain the resistance against hyperammonemia shown by neonatal rats.

Ammonia↗
PubMed2006

Role of extracellular cGMP and of hyperammonemia in the impairment of learning in rats with chronic hepatic failure. Therapeutic implications.

Hepatic encephalopathy is a complex neuropsychiatric syndrome present in patients with chronic or acute liver disease. We review here some recent advances in the study, in animal models, of the mechanisms involved in the impairment in intellectual function in hepatic encephalopathy. These studies show that the function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in rats with chronic hyperammonemia or liver failure and from patients died in hepatic encephalopathy. This impairment leads to a reduced extracellular concentration of cGMP in the cerebellum and is associated with reduced learning ability in these animal models. Moreover, learning ability of hyperammonemic rats was restored by increasing cGMP by: (1) continuous intracerebral administration of zaprinast, an inhibitor of the cGMP-degrading phosphodiesterase, (2) chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that crosses the blood-brain barrier and (3) continuous intracerebral administration of cGMP. The data summarized indicate that impairment of learning ability in rats with chronic liver failure or hyperammonemia is due to impairment of the glutamate-nitric oxide-cGMP pathway. Moreover, increasing extracellular cGMP by pharmacological means may be a new therapeutic approach to improve cognitive function in patients with hepatic encephalopathy.

Animals↗
PubMed2006

Hyperammonemia induces transport of taurine and creatine and suppresses claudin-12 gene expression in brain capillary endothelial cells in vitro.

Ammonia is a key neurotoxin involved in the neurological complications of acute liver failure. The present study was undertaken to study the effects of exposure to pathophysiologically relevant concentrations of ammonium chloride on cultured brain capillary endothelial cells in order to identify mechanisms by which ammonia may alter blood-brain barrier function. Conditionally immortalized mouse brain capillary endothelial cells (TM-BBB) were used as an in vitro model of the blood-brain barrier. Gene expression of a series of blood-brain barrier transporters and tight junction proteins was assessed by quantitative real time PCR analysis. Exposure to ammonia (5mM for 72h) resulted in significant increases in mRNA levels of taurine transporter (TAUT; 2.0-fold increase) as well as creatine transporter (CRT; 1.9-fold increase) whereas claudin-12 mRNA expression was significantly reduced to 67.7% of control levels. Furthermore, [(3)H]taurine and [(14)C]creatine uptake were concomitantly increased following exposure to ammonia, suggesting that up-regulation of both TAUT and CRT under hyperammonemic conditions results in an increased function of these two transporters in TM-BBB cells. TAUT and CRT are respectively involved in osmoregulation and energy buffering in the brain, two systems that are thought to be affected in acute liver failure. Furthermore, claudin-12 down-regulation suggests that hyperammonemia may also affect tight junction integrity. Our results provide evidence that ammonia can alter brain capillary endothelial cell gene expression and transporter function. These findings may be relevant to pathological situations involving hyperammonemia, such as liver disease.

Animals↗
PubMed2005

Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats.

Inhibition of glutamine synthesis reduces astrocyte swelling and associated physiological abnormalities during acute ammonium acetate infusion in anesthetized rats. We tested the hypothesis that inhibition of glutamine accumulation during more prolonged ammonium acetate infusion in unanesthetized rats reduces cortical astrocyte swelling and immunohistochemical changes in astrocytic proteins. Rats received a continuous i.v. infusion of either sodium acetate or ammonium acetate for 24 h to increase plasma ammonia from about 30-400 mumol/l. Cohorts were pretreated with vehicle or l-methionine-S-sulfoximine (MSO; 0.83 mmol/kg). MSO reduced glutamine synthetase activity by 57% and glutamine synthetase immunopositive cell number by 69%, and attenuated cortical glutamine accumulation by 71%. Hyperammonemia increased the number of swollen astrocytes in cortex and MSO reduced this increase to control values. The number of glial fibrillary acidic protein immunopositive cells in cortex was greater in hyperammonemic rats and the increase in superficial cortical layers was attenuated by MSO. Immunoreactivity for the gap junction protein connexin-43 in the neuropil, assessed by optical density, was greater in the hyperammonemic group compared with controls, but this increase was not attenuated by MSO. No changes in the optical density of GLT1 glutamate transporter immunoreactivity in cortex were detected in any group. We conclude that glutamine synthetase inhibition reduces astrocyte swelling and ameliorates some of the reactive astroglial cytoskeletal alterations seen at 24 h of hyperammonemia, but that gap junction changes in astrocytes occur independently of glutamine accumulation and swelling.

Animals↗
PubMed2006

A patient with arginase deficiency and episodic hyperammonemia successfully treated with menses cessation.

Arginase deficiency is an urea cycle disorder that generally presents with mental retardation and spasticity, yet uncommonly with episodes of hyperammonemia. A female adolescent with arginase deficiency developed hyperammonemic episodes temporally related to her menstrual cycle, which ceased upon adequate treatment with depot medroxy progesterone acetate. A similar case was previously reported. A catamenial trigger should be considered in adolescent female arginase-deficient patients with episodes of hyperammonemia.

Adult↗
PubMedDate not supplied

Loss of expression of glial fibrillary acidic protein in acute hyperammonemia.

Glial fibrillary acid protein (GFAP) is a major component of the glial filament network and alterations in expression of this protein in cultured astrocytes have been reported in response to acute ammonia exposure in vitro. In order to determine the effects of acute hyperammonemia in vivo on GFAP expression, brain extracts from rats with acute liver failure due to hepatic devascularization (portacaval anastomosis followed 24h later by hepatic artery ligation, HAL) were analyzed for GFAP mRNA using reverse transcription-polymerase chain reaction (RT-PCR) and appropriate oligonucleotide primers. GFAP protein was assayed by immunoblotting using a polyclonal antibody. Hepatic devascularization resulted in a significant 55-68% decrease (P<0.01) of GFAP mRNA and a concomitant loss of GFAP protein at precoma and coma stages of encephalopathy when brain water content was significantly increased and brain ammonia concentrations were in the millimolar range (1-5mM). Expression of a second glial filament protein S-100beta was unaffected by acute hyperammonemia. These findings suggest a role for GFAP in cell volume regulation and that loss of GFAP expression could contribute to the pathogenesis of brain edema in acute hyperammonemic syndromes.

Acute Disease↗
PubMedDate not supplied

Nitric oxide in hepatic encephalopathy and hyperammonemia.

Chronic alcoholism, viral hepatitis or hepatotoxic drug overdose result in liver dysfunction which may lead to a neuropsychiatric disorder termed hepatic encephalopathy (HE). Although, the exact molecular mechanisms underlying the pathophysiology of HE are not known, excitatory/inhibitory neurotransmitter imbalance leading to dysfunction of the glutamate-nitric oxide (NO) system is thought to play a major role. Activation of the NMDA subtype of glutamate receptors leads to increase in intracellular calcium, which initiates several calcium-dependent processes including NO formation. NO is a gaseous, highly reactive, freely diffusible molecule with a short half-life. Recent studies demonstrate increased expression of the neuronal isoform of NO synthase (NOS) and the uptake of L-arginine (the obligate precursor of NO) in both chronic and acute HE. Hyperammonemia associated with liver dysfunction results in increased NO, which may lead to learning and memory impairments and cerebral edema commonly seen, particularly in acute hyperammonemia.

Animals↗
PubMed2004

[Hyperinsulinism-hyperammonemia syndrome due to a de novo mutation in exon 7 (G979A) of the glutamate dehydrogenase gene with excellent response to diazoxide].

Hyperinsulinism-hyperammonemia syndrome is characterized by recurrent and symptomatic hypoglycemias in childhood, secondary to hyperinsulinism associated with mild and asymptomatic hyperammonemia. This syndrome is caused by dominantly expressed mutations of the glutamate dehydrogenase gene (10q23.3). These mutations modify control of enzyme activity and represent the second cause of congenital hyperinsulinism of known genetic etiology. Moreover, this syndrome is the first genetic disorder due to an increase of function in an enzyme of intermediary metabolism to have been identified. We present the case of a 16-month-old boy with symptomatic recurrent hypoglycemias from the end of the first year of life, caused by a de novo mutation in exon 7 (G979A) of the GDH gene, with excellent outcome after diazoxide treatment.

Diazoxide↗
PubMed2006

Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure.

In this prospective study of patients with fulminant hepatic failure (FHF), we tested the hypothesis that arterial hyperammonemia results in cerebral accumulation of the osmotic active amino acids glutamine and alanine, processes that were expected to correlate with intracranial pressure (ICP). By using in vivo brain microdialysis technique together with ICP monitoring in 17 FHF patients (10 females/7 males; median age 49 (range 18 to 66) years), we found that arterial ammonia concentration correlated to brain content of glutamine (r=0.47; P<0.05) but not to alanine. A persisting high arterial ammonia concentration (above 200 micromol/L) characterized patients who developed high ICP (n=8) while patients who did not experience surges of increased ICP (n=9) had a decline in the ammonia level (P<0.05). Moreover, brain glutamine and alanine concentrations were higher at baseline and increased further in patients who developed intracranial hypertension compared with patients who experienced no surges of high ICP. Brain glutamine concentration increased 32% from baseline to 6536 (697 to 9712) micromol/L (P<0.05), and alanine 44% from baseline to 104 (81 to 381) micromol/L (P<0.05). Brain concentration of glutamine (r=0.59, P<0.05), but not alanine, correlated to ICP. Also arterial ammonia concentration correlated to ICP (r=0.73, P<0.01). To conclude, this study shows that persistence of arterial hyperammonemia is associated with profound changes in the cerebral concentration of glutamine and alanine. The elevation of brain glutamine concentration correlated to ICP in patients with FHF.

Adolescent↗
PubMed2003

Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis.

Hyperammonemia is a universal finding after gastrointestinal hemorrhage in cirrhosis. We administered an oral amino acid solution mimicking the hemoglobin molecule to examine neuropsychological changes, brain glutamine levels, and brain magnetization transfer ratio (MTR). Forty-eight metabolically stable patients with cirrhosis and no evidence of "overt" hepatic encephalopathy (HE) were randomized to receive 75 g of amino acid solution or placebo; measurements were performed before and 4 hours after administration. Neuropsychological tests included the Trails B Test, Digit Symbol Substitution Test, memory subtest of the Randt battery, and reaction time. Plasma was collected for ammonia and amino acid measurements, and brain metabolism was studied using proton magnetic resonance (MR) spectroscopy in the first 16 randomized patients. In 7 other patients, MTR was measured. A significant increase in ammonia levels was observed in the amino acid group (amino acid group, 76 +/- 7.3 to 121 +/- 6.4 micromol/L; placebo, 83 +/- 3.3 to 78 +/- 2.9 micromol/L; P <.001). Neuropsychological function improved significantly in the placebo group, but no significant change in neuropsychological function was observed in the amino acid group. Brain glutamate/glutamine (Glx)/creatine (Cr) ratio increased significantly in the amino acid group. MTR decreased significantly from 30 +/-2.9 to 23 +/- 4 (P <.01) after administration of the amino acid solution. In conclusion, an improvement in neuropsychological test results followed placebo, which was not observed in patients administered the amino acid solution. Induced hyperammonemia resulted in an increase in brain Glx/Cr ratio and a decrease in MTR, which may indicate an increase in brain water as the operative mechanism.

Amino Acids↗
PubMed2002

Continuous venovenous hemodiafiltration in neonatal onset hyperammonemia.

We report on four cases of neonatal-onset hyperammonemia due to metabolic disorders treated with continuous hemodiafiltration (CHDF). CHDF accomplished prompt removal of serum ammonia under very stable circulation. To overcome the various difficulties of blood purification procedures to the neonate, we used: (1) a 7-Fr double lumen catheter from the internal jugular vein to the atrium to perform the procedure veno-venously, (2) a special circuit for neonates, (3) nafamostat mesilate as an anticoagulant, and (4) a circuit warmer. The serum ammonium level decreased under 200 microg/dL within 30 hours and lactic acidosis were corrected immediately. We conclude that CHDF is an extremely effective and safe treatment for fluminant neonatal-onset hyperammonemia due to metabolic disorders.

Adult↗